(181 days)
The FilmArray® Pneumonia Panel plus is a multiplexed nucleic acid test intended for use with FilmArray® 2.0, or FilmArray® Torch systems for the simultaneous detection of nucleic acids from Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and multiple respiratory viral and bacterial nucleic acids, as well as select antimicrobial resistance genes. in sputum-like specimens (induced or expectorated sputum, or endotracheal aspirates) or bronchoalveolar lavage (BAL)-like specimens (BAL) obtained from individuals meeting MERS-CoV clinical and/or epidemiological criteria.
Testing with FilmArray Pneumonia Panel plus should not be performed unless the patient meets clinical and/or epidemiologic criteria for testing suspecimens. This includes: clinical signs and symptoms associated with MERS-CoV infection, contact with a probable or confirmed MERS-CoV case, history of travel to geographic locations where MERS-CoV cases were detected, or other epidemiological links for which MERS-CoV testing may be indicated.
The following bacteria are reported semi-quantitatively with bins representing approximately 10^4, 10^5, 10^6, or ≥10^7 genomic copies of bacterial nucleic acid per milliliter (copies/mL) of specimen, to aid in estimating relative abundance of nucleic acid from these common bacteria within a specimen:
Bacteria reported with bins of 10^4, 10^5, 10^6, or ≥10^7 copies/mL
- Acinetobacter calcoaceticus-baumannii complex
- Enterobacter cloacae complex
- · Escherichia coli
- · Haemophilus influenza
- Klebsiella aerogenes
- · Klebsiella oxytoca
- · Klebsiella pneumoniae group
- Moraxella catarrhalis
- · Proteus spp.
- Pseudomonas aeruginosa
- · Serratia marcescens
- Staphylococcus aureus
- Streptococcus agalactiae
- Streptococcus pneumoniae
- · Streptococcus pyogenes
The following atypical bacteria, viruses, and antimicrobial resistance genes are reported qualitatively:
Atypical Bacteria
- Chlamydia pneumoniae
- · Legionella pneumophila
- Mycoplasma pneumoniae
Viruses
- · Adenovirus
- · Coronavirus
- Human Metapneumovirus
- · Human Rhinovirus/Enterovirus
- · Influenza A
- · Influenza B
- · Parainfluenza Virus
- · Respiratory Syncytial Virus
Antimicrobial Resistance Genes
- · CTX-M
- IMP
- КРС
- NDM
- OXA-48-like
- VIM
- · mecA/C and MREJ
The detection and identification of specific viral and bacterial nucleic acids from MERS-CoV and other respiratory pathogens, as well as the estimation of relative abundance of nucleic acid from common bacterial analytes, within specimens collected from individuals meeting MERS-CoV clinical and/or epidemiological criteria aids in the differential diagnosis of MERS-CoV infection, if used in conjunction with other clinical and epidemiological information in accordance with the guidelines provided by the appropriate public health authorities.
FilmArray Pneumonia Panel plus MERS-CoV positive results are for the presumptive identification of MERS-CoV. The definitive identification of MERS-CoV requires additional testing and confirmation procedures in consultation with the appropriate public health authorities (e.g., local or state public health departments, etc.) for whom reporting is necessary. The diagnosis of MERS-CoV infection must be made based on history, signs, symptoms, exposure likelihood, and other laboratory evidence in addition to the identification of MERS-CoV.
FilmArray Pneumonia Panel plus MERS-CoV negative results, even in the context of a FilmArray Pneumonia Panel plus positive result for one or more of the common respiratory pathogens, do not preclude MERS-CoV infection and should not be used as the sole basis for patient management decisions. The levels of MERS-CoV that would be present in sputum-like or BAL-like specimens from individuals with early infection and from asymptomatic MERS-CoV carriers are not well understood. A negative FilmArray Pneumonia Panel plus MERS-CoV result in an asymptomatic individual does not rule out the possibility of future illness and does not demonstrate that the individual is not infectious.
Viral culture should not be attempted on specimens with positive FilmArray Pneumonia Panel plus results for MERS-CoV unless a BSL 3 facility is available to receive and culture specimens.
Negative results in the setting of a respiratory illness may be due to infection with pathogens that are not detected by this test, pathogens below the limit of detection, or in the case of bacterial analytes, present at levels below the lowest reported 10^4 copies/mL bin. Detection of analytes does not rule out co-infection with other organisms; the agent(s) detected by the FilmArray Pneumonia Panel plus may not be the definite cause of disease. Additional laboratory testing (e.g. bacterial and viral culture, immunofluorescence, and radiography) may be necessary when evaluating a patient with possible lower respiratory tract infection.
Detection of bacterial nucleic acid may be indicative of colonizing or normal respiratory flora and may not indicate the causative agent of pneumonia. Semi-quantitative Bin (copies/mL) results generated by the FilmArray Pneumonia Panel plus are not equivalent to CFU/mL and do not consistently correlate with the quantity of bacterial analytes compared to CFUmL. For specimens with multiple bacteria detected, the relative abundance of nucleic acids (copies/mL) may not correlate with the relative abundance of bacteria as determined by culture (CFU/mL). Clinical correlation is advised to determine significance of semi-quantitative Bin (copies/mL) for clinical management.
The antimicrobial resistance gene detected may or may not be associated with the agent(s) responsible for disease. Negative results for these antimicrobial resistance gene assays do not indicate susceptibility to corresponding classes of antimicrobials, as multiple mechanisms of antimicrobial resistance exist.
Antimicrobial resistance can occur via multiple mechanisms. A "Not Detected" result for a genetic marker of antimicrobial resistance does not indicate susceptibility to associated antimicrobial drugs or drug classes. A "Detected" result for a genetic marker of antimicrobial resistance cannot be definitively linked to the microorganism(s) detected. Culture is required to obtain isolates for antimicrobial susceptibility testing, and FilmArray Pneumonia Panel plus results should be used in conjunction with culture results for deterial susceptibility or resistance.
Due to the genetic similarity between human rhinovirus and enterovirus, the test cannot reliably differentiate them. A positive Rhinovirus/Enterovirus result should be followed up using an alternate method (e.g., cell culture or sequence analysis) if differentiation is required.
Culture is required to identify pathogens not detected by the FilmArray Panel plus, to further speciate analytes in genus, complex, or group results if desired, to identify bacterial pathogens present below the 10^4 copies/mL bin if desired, and for antimicrobial susceptibility testing.
The FilmArray Pneumonia Panel plus is designed to simultaneously identify Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and 26 other potential pathogens of lower respiratory tract infection (LRTI) and seven associated antimicrobial resistance (AMR) genes from a sputum-like (induced and expectorated sputum as well as endotracheal aspirate, ETA) or bronchoalveolar lavage (BAL)-like (BAL and mini-BAL) specimens obtained from individuals meeting MERS-CoV clinical and/or epidemiological criteria in a time (~1 hour) that allows the test results to be used in determining appropriate patient treatment and management.
The FilmArray Pneumonia Panel plus is compatible with BioFire's PCR-based in vitro diagnostic FilmArray, FilmArray 2.0, and FilmArray Torch systems for infectious disease testing. A specific software module (i.e. FilmArray Pneumonia Panel pouch module) is used to perform FilmArray Pneumonia Panel testing on these systems.
A test is initiated by loading Hydration Solution into one port of the FilmArray pouch and a sputum-like or BAL-like sample mixed with the provided Sample Buffer into the other port of the FilmArray Pneumonia Panel plus pouch and placing it in a FilmArray instrument. The pouch contains all of the reagents required for specimen testing and analysis in a freeze-dried format; the addition of Hydration Solution and Sample/Buffer Mix rehydrates the reagents. After the pouch is prepared, the FilmArray Software guides the user through the steps of placing the instrument, scanning the pouch barcode, entering the sample identification, and initiating the run.
The FilmArray instruments contain coordinated systems of inflatable bladders and seal points, which act on the pouch to control the movement of liquid between the pouch blisters. When a bladder is inflated over a reagent blister, it forces liquid from the blister into connecting channels. Alternatively, when a seal is placed over a connecting channel it acts as a valve to open or close a channel. In addition, electronicallycontrolled pneumatic pistons are positioned over multiple plungers in order to deliver the rehydrated reagents into the blisters at the appropriate times. Two Peltier devices control heating and cooling of the pouch to drive the PCR reactions and the melt curve analysis.
Nucleic acid extraction occurs within the FilmArray pouch using mechanical and chemical lysis followed by purification using standard magnetic bead technology. After extracting and purifying nucleic acids from the unprocessed sample, the FilmArray performs a nested multiplex PCR that is executed in two stages. During the first stage, the FilmArray performs a single, large volume, highly multiplexed reverse transcription PCR (rt-PCR) reaction. The products from first stage PCR are then diluted and combined with a fresh, primer-free master mix and a fluorescent double stranded DNA binding dye (LC Green® Plus, BioFire Diagnostics). The solution is then distributed to each well of the array. Array wells contain sets of primers designed specifically to amplify sequences internal to the PCR products generated during the first stage PCR reaction. The 2nd stage PCR, or nested PCR, is performed in singleplex fashion in each well of the array. At the conclusion of the 2nd stage PCR, the array is interrogated by melt curve analysis for the detection of signature amplicons denoting the presence of specific targets. A digital camera placed in front of the 2nd stage PCR captures fluorescent images of the PCR reactions and software interprets the data.
The FilmArray Software automatically interprets the results of each DNA melt curve analysis and combines the data with the results of the internal pouch controls to provide a test result for each organism on the panel.
A new feature of the FilmArray Pneumonia Panel plus is the reporting of organism abundance for common bacteria in discrete bins representing 10^4, 10^5, 10^6, and ≥10^7 genomic copies/mL. The panel accomplishes this by comparing the amplification of the bacterial assays with that of a Quantified Standard Material (QSM) present in the pouch.
The provided text describes the performance study for the FilmArray Pneumonia Panel plus, a multiplex nucleic acid test. Below is a structured summary addressing the requested points.
Acceptance Criteria and Device Performance Study
The acceptance criteria for the FilmArray Pneumonia Panel plus are indirectly demonstrated through the clinical and analytical performance studies, showing the device's ability to accurately detect a wide range of respiratory pathogens and antimicrobial resistance genes in specific clinical samples. The study proves the device meets these criteria through robust empirical testing and in silico analyses.
1. Table of Acceptance Criteria and Reported Device Performance
The document doesn't explicitly state "acceptance criteria" in a go/no-go format for each analyte, but rather presents the performance (Sensitivity/PPA and Specificity/NPA) from the clinical study as evidence of meeting regulatory requirements. The implicit acceptance criteria would likely be high agreement percentages and confidence intervals.
Table 1: Summary of Reported Device Performance (Clinical Study - BAL Specimens)
| Analyte | Reference Method | Sensitivity/PPA (%) | 95% CI (Sensitivity/PPA) | Specificity/NPA (%) | 95% CI (Specificity/NPA) |
|---|---|---|---|---|---|
| MERS-CoV | PCR/Seq | - | - | 100 | 99.5-100% |
| Acinetobacter calcoaceticus-baumannii complex | qRefCx | - | - | 99.2 | 98.3-99.6% |
| Enterobacter cloacae complex | qRefCx | 91.7 | 64.6-98.5% | 98.6 | 97.5-99.2% |
| Escherichia coli | qRefCx | 100 | 75.8-100% | 99.0 | 98.1-99.5% |
| Haemophilus influenzae | qRefCx | 100 | 72.2-100% | 91.4 | 89.3-93.1% |
| Klebsiella aerogenes | qRefCx | 85.7 | 48.7-97.4% | 99.2 | 98.3-99.6% |
| Klebsiella oxytoca | qRefCx | 100 | 34.2-100% | 98.9 | 98.0-99.4% |
| Klebsiella pneumoniae group | qRefCx | 100 | 79.6-100% | 98.6 | 97.5-99.2% |
| Moraxella catarrhalis | qRefCx | - | - | 96.6 | 95.1-97.6% |
| Proteus spp. | qRefCx | 100 | 56.6-100% | 99.5 | 98.8-99.8% |
| Pseudomonas aeruginosa | qRefCx | 100 | 90.4-100% | 95.3 | 93.6-96.6% |
| Serratia marcescens | qRefCx | 100 | 61.0-100% | 99.3 | 98.5-99.7% |
| Staphylococcus aureus | qRefCx | 97.9 | 88.9-99.6% | 91.2 | 89.1-93.0% |
| Streptococcus agalactiae | qRefCx | 100 | - | 97.2 | 95.8-98.1% |
| Streptococcus pneumoniae | qRefCx | 100 | 56.6-100% | 97.1 | 95.8-98.1% |
| Streptococcus pyogenes | qRefCx | 100 | 34.2-100% | 99.3 | 98.5-99.7% |
| Chlamydia pneumoniae | PCR/Seq | - | - | 99.9 | 99.3-100% |
| Legionella pneumophila | PCR/Seq | 100 | 34.2-100% | 100 | 99.5-100% |
| Mycoplasma pneumoniae | PCR/Seq | 100 | 43.9-100% | 99.9 | 99.3-100% |
| Adenovirus | PCR/Seq | 100 | 67.6-100% | 100 | 99.5-100% |
| Coronavirus | PCR/Seq | 85.7 | 65.4-95.0% | 98.4 | 97.3-99.1% |
| Human Metapneumovirus | PCR/Seq | 100 | 67.6-100% | 99.9 | 99.3-100% |
| Human Rhinovirus/Enterovirus | PCR/Seq | 96.3 | 87.5-99.0% | 98.6 | 97.5-99.2% |
| Influenza A | PCR/Seq | 100 | 72.2-100% | 99.6 | 98.9-99.9% |
| Influenza B | PCR/Seq | 83.3 | 43.6-97.0% | 99.9 | 99.3-100% |
| Parainfluenza Virus | PCR/Seq | 88.9 | 67.2-96.9% | 99.8 | 99.1-99.9% |
| Respiratory Syncytial Virus | PCR/Seq | 100 | 43.9-100% | 100 | 99.5-100% |
| CTX-M (AMR Gene) | qMol | 85.7 | 48.7-97.4% | 100 | 97.4-100% |
| IMP (AMR Gene) | qMol | - | - | 100 | 97.5-100% |
| KPC (AMR Gene) | qMol | 100 | 34.2-100% | 99.3 | 96.3-99.9% |
| mecA/C and MREJ (AMR Gene) | qMol | 88.9 | 76.5-95.2% | 91.4 | 82.5-96.0% |
| NDM (AMR Gene) | qMol | 0 | - | 99.3 | 96.3-99.9% |
| OXA-48-like (AMR Gene) | qMol | - | - | 100 | 96.0-100% |
| VIM (AMR Gene) | qMol | - | - | 100 | 97.5-100% |
Note: Performance for Sputum specimens presented in Table 5.
Note: PPA = Positive Percent Agreement (Sensitivity), NPA = Negative Percent Agreement (Specificity).
Note: '-' indicates TP/(TP+FN) or TN/(TN+FP) was 0/0, thus percentage and CI could not be calculated.
2. Sample Sizes and Data Provenance
- Test Set (Clinical Performance):
- Sample Size: 846 BAL specimens (including mini-BAL) and 836 sputum specimens (including ETA).
- Data Provenance: Multi-center study conducted at eight geographically distinct U.S. study sites. The study was prospective in nature, collecting specimens from October 2016 to July 2017. Additionally, archived retrospective specimens were used for low-prevalence analytes, including 8 BAL and 10 sputum specimens from a 2015 MERS-CoV outbreak in South Korea, and 171 archived specimens from external laboratories (139 BAL, 14 sputum, and negative controls). Contrived specimens were also used (1225 total, N=625 BAL, N=600 sputum for main contrived study; N=60 BAL, N=60 sputum for polymicrobial contrived study).
3. Number of Experts and Qualifications for Ground Truth
The document does not specify the exact number and qualifications of experts establishing the ground truth for the test set. Instead, it details the reference methods used for ground truth:
- Bacterial Analytes: Quantitative reference culture (qRefCx) with a threshold of ≥ 3162 (10^3.5) CFU/mL. Discrepancies were further investigated using single PCR assays followed by quantitative molecular assay including sequencing (qMol), and additional molecular assays followed by sequence analysis where needed.
- Atypical Bacteria and Viruses: Two conventional PCR assays followed by bidirectional sequencing. A specimen was considered positive if bidirectional sequencing data met predefined quality acceptance criteria and matched organism-specific sequences in the NCBI GenBank database.
- AMR Genes: Single PCR assay followed by sequencing (qMol) from the specimen, combined with phenotypic AST (antimicrobial susceptibility testing) via qRefCx performed in conjunction with current CLSI guidelines for correlation.
- MERS-CoV: For clinical specimens, it was assumed they were negative as the virus was not circulating in the US during enrollment. For archived specimens, previous laboratory results (from South Korea during the 2015 outbreak) served as ground truth.
4. Adjudication Method for the Test Set
The adjudication method for discrepant results between the FilmArray Pneumonia Panel plus and the primary comparator method varied:
- For bacterial analytes, discrepancies were first examined to see if the qRefCx or FilmArray observed the analyte but below the detection threshold. If unresolved, qMol testing results were considered. If still unresolved, multiple additional molecular assays followed by sequence analysis were used.
- For other analytes (atypical bacteria, viruses, AMR genes), molecular comparator results (two conventional PCR assays followed by bidirectional sequencing) were used. If the two assays agreed, that was the ground truth. If they disagreed, additional molecular assays followed by sequence analysis were performed. The results of "SOC testing" (Standard of Care) were also considered.
This suggests an algorithm-mediated adjudication with expert review for difficult cases (discrepancies), rather than a fixed "2+1" or "3+1" expert consensus model initially. The ground truth itself often involved molecular methods, which are considered highly accurate for nucleic acid detection.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
There is no MRMC comparative effectiveness study described in the provided text. The study focuses on comparing the device's performance against reference laboratory methods (molecular and culture-based) for direct detection, not on evaluating how human readers' performance might improve with or without AI assistance. The device is an in vitro diagnostic (IVD) test, not an AI-assisted diagnostic imaging tool.
6. Standalone (Algorithm Only) Performance
The entire performance study described is essentially a standalone (algorithm only without human-in-the-loop) performance evaluation for the FilmArray Pneumonia Panel plus. The results for sensitivity/PPA and specificity/NPA directly report the device's accuracy in detecting various pathogens and AMR genes compared to established reference methods.
7. Type of Ground Truth Used
The ground truth used varied by analyte:
- Bacterial Analytes: Quantitative Reference Culture (qRefCx) for primary evaluation. Discrepancies were resolved using quantitative molecular assays (qMol) and subsequent sequencing/additional molecular assays.
- Atypical Bacteria, Viruses (excluding MERS-CoV in US clinical samples): Two conventional PCR assays followed by bidirectional sequencing. Discrepancies resolved with additional molecular assays and sequencing.
- MERS-CoV (archived specimens): Previous laboratory results (implicitly molecular/viral culture confirmation) from the outbreak.
- Antimicrobial Resistance Genes: Single PCR assay followed by sequencing (qMol) directly from the specimen, and correlation with phenotypic AST from cultured isolates.
Therefore, the ground truth is a combination of expert-interpreted molecular data (PCR/sequencing), quantitative culture, and phenotypic AST, with further discrepancy resolution protocols.
8. Sample Size for the Training Set
The document focuses solely on the performance evaluation of the FilmArray Pneumonia Panel plus device. It states that the device is "designed to simultaneously identify Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and 26 other potential pathogens of lower respiratory tract infection (LRTI) and seven associated antimicrobial resistance (AMR) genes." It describes analytical and clinical validation studies but does not provide information on a "training set" sample size for an AI/ML model, as this is a molecular diagnostic device not explicitly using an AI/ML component in its core diagnostic algorithm. The phrase "FilmArray Software automatically interprets the results" implies a deterministic algorithm, not a trainable machine learning model.
9. How the Ground Truth for the Training Set was Established
Since no training set for an AI/ML model is mentioned, there is no information provided on how its ground truth was established. The document describes the validation/test set ground truth as outlined in point 7.
§ 866.4001 A multiplex respiratory panel to detect and identify emerging respiratory pathogen(s) and common respiratory pathogens in human clinical specimens.
(a)
Identification. A multiplex respiratory panel to detect and identify emerging respiratory pathogen(s) and common respiratory pathogens in human clinical specimens is identified as an in vitro diagnostic device intended for the qualitative detection and identification of both emerging and common respiratory pathogens from individuals meeting specific emerging respiratory pathogen clinical and/or epidemiological criteria. For example, clinical signs and symptoms associated with infection of the emerging respiratory pathogen, contact with a probable or confirmed emerging respiratory pathogen case, history of travel to geographic locations where cases of the emerging respiratory pathogen were detected, or other epidemiological links for which testing of the emerging respiratory pathogen may be indicated. A device to detect and identify emerging respiratory pathogen(s) and common respiratory pathogens in human clinical specimens, and in turn to distinguish emerging respiratory pathogen(s) from common respiratory pathogens, is intended to aid in the differential diagnosis of the emerging respiratory pathogen infection, in conjunction with other clinical, epidemiologic, and laboratory data, in accordance with the guidelines provided by the appropriate public health authorities.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The intended use for the labeling required under § 809.10 of this chapter must include a description of what the device detects and measures, the specimen types, the results provided to the user, the clinical indications for which the test is to be used, the specific intended population(s), the testing location(s) where the device is to be used (if applicable), and other conditions of use as appropriate.
(2) The labeling required under § 809.10 of this chapter must include:
(i) A device description, including the parts that make up the device, ancillary reagents required but not provided, and an explanation of the methodology.
(ii) Performance characteristics from analytical studies, including cut-off (if applicable), analytical sensitivity (
i.e., limit of detection), inclusivity, reproducibility, interference, cross-reactivity, instrument carryover/cross-contamination (if applicable), and specimen stability.(iii) Detailed instructions for minimizing the risk of potential users' exposure to the emerging respiratory pathogen(s) that may be present in test specimens and those used as control materials.
(iv) Detailed instructions for minimizing the risk of generating false positive test results due to carry-over contamination from positive test specimens and/or positive control materials.
(v) A warning statement that the interpretation of test results requires experienced healthcare professionals who have training in principles and use of infectious disease diagnostics and reporting of results, in conjunction with the patient's medical history, clinical signs and symptoms, and the results of other diagnostic tests.
(vi) A warning statement that culture should not be attempted in cases of positive results for an emerging respiratory pathogen unless a facility with an appropriate level of laboratory biosafety (
e.g., BSL 3 and BSL 3+) is available to receive and culture specimens.(vii) A warning statement that device positive results for one or more common respiratory pathogens do not rule out bacterial infection, or co-infection with other common respiratory pathogens.
(viii) A warning statement that respiratory pathogen(s) detected may not be the definite cause of disease.
(ix) A warning statement that the use of additional laboratory testing (
e.g. bacterial culture, immunofluorescence, x-ray findings) and clinical presentation must be taken into consideration in order to obtain the final diagnosis of a respiratory infection.(x) A limiting statement that device negative results for the common respiratory pathogens do not preclude infection of a respiratory pathogen and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions.
(xi) A limiting statement that analyte targets (
e.g., pathogen nucleic acid sequences or other molecular signatures) may persist in vivo, independent of organism viability. Detection of analyte target(s) does not imply that the corresponding pathogen(s) is infectious, nor is the causative agent(s) for clinical symptoms.(xii) A limiting statement that detection of pathogen nucleic acid sequences or other molecular signatures is dependent upon proper specimen collection, handling, transportation, storage and preparation. Failure to observe proper procedures in any one of these steps can lead to incorrect results. There is a risk of false negative values resulting from improperly collected, transported, or handled specimens.
(xiii) A limiting statement that there is a risk of false positive values resulting from cross-contamination by target organisms, their nucleic acids or amplified product, or from non-specific signals in the assay.
(xiv) A limiting statement that there is a risk of false negative results due to the presence of nucleic acid sequence variants in the pathogen targets of the device.
(xv) A limiting statement that device performance was not established in immunocompromised patients.
(xvi) A limiting statement that positive and negative predictive values are highly dependent on prevalence. The device performance was established during one or more specific respiratory seasons. The performance for some respiratory pathogens may vary depending on the prevalence and patient population tested. False positive test results are likely when prevalence of disease due to a particular respiratory pathogen is low or non-existent in a community.
(xvii) In situations where the performance of the device was estimated based largely on testing pre-selected banked retrospective clinical specimens and/or contrived clinical specimen, a limiting statement that the estimated device performance of that specific pathogen or pathogen subtype may not reflect the performance or prevalence in the intended use population.
(xviii) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that testing with the device should not be performed unless the patient meets clinical and/or epidemiologic criteria for testing suspected specimens of the emerging respiratory pathogen.
(xix) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that positive results obtained with the device for the emerging respiratory pathogen are for the presumptive identification of that pathogen and that the definitive identification of the emerging respiratory pathogen requires additional testing and confirmation procedures in consultation with the appropriate public health authorities (
e.g., local or state public health departments) for whom reporting is necessary.(xx) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that negative results for the emerging respiratory pathogen, even in the context of device positive results for one or more of the common respiratory pathogens, do not preclude infection with the emerging respiratory pathogen and should not be used as the sole basis for patient management decisions.
(xxi) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that negative results for the emerging respiratory pathogen may be due to infection of the emerging respiratory pathogen at a specific respiratory tract location that may not be detected by a particular clinical specimen type. A negative result for the emerging respiratory pathogen in an asymptomatic individual does not rule out the possibility of future illness and does not demonstrate that the individual is not infectious.
(xxii) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that a nationally notifiable Rare Disease of Public Health Significance caused by an emerging respiratory pathogen must be reported, as appropriate, to public health authorities in accordance with local, state, and federal law.
(3) Design verification and validation must include:
(i) Performance results of an appropriate clinical study (
e.g., a prospective clinical study) for each specimen type, and, if appropriate, results from additional characterized samples. The clinical study must be performed on a study population consistent with the intended use population and must compare the device performance to results obtained using FDA-accepted comparator methods or to expected negative results if the infection is not generally expected in the intended use population. Clinical specimens evaluated in the study must contain relevant organism concentrations applicable to the specimen type(s) and the targeted analyte(s). Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.(ii) For devices with an intended use that includes detection of emerging respiratory pathogen(s) for which an FDA recommended panel is available, design verification and validation must include the performance results of an analytical study testing an FDA recommended reference panel of characterized samples that contain the emerging respiratory pathogen. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.
(iii) An appropriate risk mitigation strategy, including a detailed description of all procedures and methods, for the post-market identification of genetic mutations and/or novel respiratory pathogen isolates or strains (
e.g., regular review of published literature and annual in silico analysis of target sequences to detect possible mismatches. The required documentation for this device must also include all of the results, including any findings, from the application of this post-market mitigation strategy.(iv) For devices with an intended use that includes detection of multiple common respiratory pathogens, in addition to detecting emerging respiratory pathogen(s) in human clinical specimens, a detailed description of the identity, phylogenetic relationship, or other recognized characterization of the common respiratory pathogens that the device is designed to detect is addressed. Also, address in detail how the device results might be used in a diagnostic algorithm and other measures that might be needed for a laboratory diagnosis of respiratory tract infection. Perform an evaluation of the device compared to a currently appropriate and FDA accepted comparator method. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.
(v) A detailed device description, including the parts that make up the device, ancillary reagents required but not provided, and a detailed explanation of the methodology, including molecular target(s) for each analyte, design of target detection reagents, rationale for target selection, limiting factors of the device (
e.g., saturation level of hybridization and maximum amplification and detection cycle number), internal and external controls, and computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported signal and result), as applicable and appropriate.(vi) A detailed description of the device software, including software applications and hardware-based devices that incorporate software.
(vii) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiate between the Influenza A virus subtypes in human clinical specimens, in addition to detecting emerging respiratory pathogen(s), a detailed description of the identity, phylogenetic relationship, or other recognized characterization of the Influenza A and B viruses that the device is designed to detect, a description of how the device results might be used in a diagnostic algorithm and other measures that might be needed for a laboratory identification of Influenza A or B virus and of specific Influenza A virus subtypes, and a description of the clinical and epidemiological parameters that are relevant to a patient case diagnosis of Influenza A or B and of specific Influenza A virus subtypes. Perform an evaluation of the device compared to a currently appropriate and FDA accepted comparator method. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.
(4) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiate between the Influenza A virus subtypes in human clinical specimens, in addition to detecting emerging respiratory pathogen(s), the labeling required under § 809.10 of this chapter must include the following:
(i) Where applicable, a limiting statement that performance characteristics for Influenza A were established when Influenza A/H3 and A/H1-2009 (or other pertinent Influenza A subtypes) were the predominant Influenza A viruses in circulation. When other Influenza A viruses are emerging, performance characteristics may vary.
(ii) Where applicable, a warning statement that reads if infection with a novel Influenza A virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent influenza viruses and sent to state or local health departments for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.
(iii) Where the device results interpretation involves combining the outputs of several targets to get the final results, such as a device that both detects Influenza A and differentiates all known Influenza A subtypes that are currently circulating, the device's labeling required under § 809.10(b)(9) of this chapter must include a clear interpretation instruction for all valid and invalid output combinations, and recommendations for any required follow up actions or retesting in the case of an unusual or unexpected device result.
(iv) A limiting statement that if a specimen yields a positive result for Influenza A, but produces negative test results for all specific influenza A subtypes intended to be differentiated (
e.g., H1-2009 and H3), this result requires notification of appropriate local, state, or federal public health authorities to determine necessary measures for verification and to further determine whether the specimen represents a novel strain of Influenza A.(5) The manufacturer must perform annual analytical reactivity testing of the device with contemporary influenza strains. This annual analytical reactivity testing must meet the following criteria:
(i) The appropriate strains to be tested will be identified by FDA in consultation with the Centers for Disease Control and Prevention (CDC) and sourced from CDC or an FDA designated source. If the annual strains are not available from CDC, FDA will identify an alternative source for obtaining the requisite strains.
(ii) The testing must be conducted according to a standardized protocol considered and determined by FDA to be acceptable and appropriate.
(iii) By July 31 of each calendar year, the results of the last 3 years of annual analytical reactivity testing must be included as part of the device's labeling. If a device has not been on the market long enough for 3 years of annual analytical reactivity testing to have been conducted since the device received marketing authorization from FDA, then the results of every annual analytical reactivity testing since the device received marketing authorization from FDA must be included. The results must be presented as part of the device's labeling in a tabular format, which includes the detailed information for each virus tested as described in the certificate of authentication, either by:
(A) Placing the results directly in the device's labeling required under § 809.10(b) of this chapter that physically accompanies the device in a separate section of the labeling where the analytical reactivity testing data can be found; or
(B) In the device's label or in other labeling that physically accompanies the device, prominently providing a hyperlink to the manufacturer's public website where the analytical reactivity testing data can be found. The manufacturer's home page, as well as the primary part of the manufacturer's website that discusses the device, must provide a prominently placed hyperlink to the web page containing this information and must allow unrestricted viewing access.
(6) If one of the actions listed at section 564(b)(1)(A)-(D) of the FD&C Act occurs with respect to an influenza viral strain, or if the Secretary of Health and Human Services (HHS) determines, under section 319(a) of the Public Health Service Act, that a disease or disorder presents a public health emergency, or that a public health emergency otherwise exists, with respect to an influenza viral strain:
(i) Within 30 days from the date that FDA notifies manufacturers that characterized viral samples are available for test evaluation, the manufacturer must have testing performed on the device with those viral samples in accordance with a standardized protocol considered and determined by FDA to be acceptable and appropriate. The procedure and location of testing may depend on the nature of the emerging virus.
(ii) Within 60 days from the date that FDA notifies manufacturers that characterized viral samples are available for test evaluation and continuing until 3 years from that date, the results of the influenza emergency analytical reactivity testing, including the detailed information for the virus tested as described in the certificate of authentication, must be included as part of the device's labeling in a tabular format, either by:
(A) Placing the results directly in the device's labeling required under § 809.10(b) of this chapter that physically accompanies the device in a separate section of the labeling where analytical reactivity testing data can be found, but separate from the annual analytical reactivity testing results; or
(B) In a section of the device's label or in other labeling that physically accompanies the device, prominently providing a hyperlink to the manufacturer's public website where the analytical reactivity testing data can be found. The manufacturer's home page, as well as the primary part of the manufacturer's website that discusses the device, must provide a prominently placed hyperlink to the web page containing this information and must allow unrestricted viewing access.