FDA 510(k) Search - By Innolitics (SaMD and AI Experts)

The BIOFIRE® SPOTFIRE® Respiratory/Sore Throat (R/ST) Panel is a multiplexed polymerase chain reaction (PCR) test intended for use with the BIOFIRE® System for the simultaneous, qualitative detection and identification of multiple respiratory viral and bacterial nucleic acids in nasopharyngeal swab (NPS) specimens obtained from individuals with signs and symptoms of respiratory tract infection, including COVID-19; (Respiratory menu) or in throat swab (TS) specimens from individuals with signs and symptoms of pharyngitis (Sore Throat menu).

The following organism types and subtypes are identified and differentiated using the SPOTFIRE R/ST Panel:

Respiratory Menu Viruses Adenovirus Coronavirus SARS-CoV-2 Coronavirus (seasonal) Human metapneumovirus Human rhinovirus/enterovirus Influenza A virus Influenza A virus/H1-2009 Influenza A virus/ H3 Influenza B virus Parainfluenza virus Respiratory syncytial virus

Bacteria Bordetella parapertussis Bordetella pertussis Chlamydia pneumoniae Mycoplasma pneumoniae
Sore Throat Menu Viruses Adenovirus Coronavirus (seasonal) Human metapneumovirus Human rhinovirus/enterovirus Influenza A virus Influenza A virus/H1-2009 Influenza A virus/H3 Influenza B virus Parainfluenza virus Respiratory syncytial virus

Bacteria Chlamydia pneumoniae Mycoplasma pneumoniae Streptococcus dysgalactiae (Group C/G Strep) Streptococcus pyogenes (Group A Strep)

Nucleic acids from the viral and bacterial organisms identified by this test are generally detectable in NPS/TS specimens during the acute phase of infection and identification of specific viral and bacterial nucleic acids from individuals exhibiting signs and symptoms of respiratory infection and/or pharyngtis are indicative of the identified microorganism and aids in diagnosis if used in conjunction with other clinical and epidemiological information, and laboratory findings. The results of this test should not be used as the sole basis for diagnosis, treatment, or other patient management decisions.

Negative results in the setting of a respiratory illness and/or pharyngitis may be due to infection with pathogens that are not detected by this test, or a respiratory tract infection that may not be detected by an NPS or TS specimen. Positive results do not rule out coinfection with other organisms. The agent(s) detected by the SPOTFIRE R/ST Panel 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 respiratory tract infection and/or pharyngitis.

Device Description

The SPOTFIRE R/ST Panel simultaneously identifies 15 different respiratory viral and bacterial pathogens in nasopharyngeal swabs (NPS) or 14 viral and bacterial pharyngitis pathogens in throat swabs (TS) from individuals with signs and symptoms of respiratory tract infections or pharyngitis, respectively, (see Intended Use:). The SPOTFIRE R/ST Panel is compatible with the SPOTFIRE System, a polymerase chain reaction (PCR)-based in vitro diagnostic system for infectious disease testing. The SPOTFIRE System Software executes the SPOTFIRE R/ST Panel test and interprets and reports the test results. The SPOTFIRE RIST Panel was designed to be used in CLIA-waived environments. A test is initiated by loading Hydration Solution into one port of the SPOTFIRE R/ST Panel pouch and NPS or TS specimen, mixed with the provided Sample Buffer, into the port of the SPOTFIRE R/ST Panel pouch and placing it in the SPOTFIRE System. 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 SPOTFIRE System Software guides the user through the steps of placing the instrument, scanning the pouch barcode, entering the sample identification, and initiating the run.

The SPOTFIRE System contains coordinated systems of inflatable bladders and seal points, which act on the pouch to control the movement of liguid between the pouch blisters. When a bladder is inflated over a reagent blister, it forces liguid 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, electronically controlled pneumatic pistons are positioned over multiple plungers in order to deliver the rehydrated reagents into the blisters at the appropriate times. Two Peltier and cooling of the pouch to drive the PCR reactions and the melt curve analysis.

Nucleic acid extraction occurs within the SPOTFIRE R/ST Panel 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 SPOTFIRE System performs a nested multiplex PCR that is executed in two stage, the SPOTFIRE System 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 doublestranded 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, 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 SPOTFIRE System Software automatically interprets the results of each DNA met curve analysis and combines the data with the results of the internal pouch controls to provide a test result for each organism on the SPOTFIRE R/ST Panel.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study proving the device meets those criteria, based on the provided FDA 510(k) summary for the BIOFIRE® SPOTFIRE® Respiratory/Sore Throat (R/ST) Panel:

The document describes the BIOFIRE® SPOTFIRE® Respiratory/Sore Throat (R/ST) Panel, a multiplexed PCR test for simultaneous, qualitative detection and identification of multiple respiratory viral and bacterial nucleic acids. The data presented primarily focuses on analytical performance and clinical performance to demonstrate substantial equivalence to a predicate device.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are generally implied by the performance metrics reported, specifically the Positive Percent Agreement (PPA) / Sensitivity and Negative Percent Agreement (NPA) / Specificity. For analytical studies, acceptance criteria related to percentages of positive results and agreement levels are explicitly stated.

Clinical Performance Acceptance Criteria (Implied by Data Reported):
For each analyte, the acceptance criteria are generally to achieve high PPA and NPA. While specific numerical thresholds for PPA/NPA are not explicitly listed as "acceptance criteria" in the clinical tables themselves, the FDA's clearance implies that the presented performance met their internal requirements for substantial equivalence. For diagnostic tests, generally, PPA and NPA values in the high 90s are expected.

Analytical Performance Acceptance Criteria and Reported Performance:

Study	Acceptance Criteria	Reported Device Performance and Conclusion
Clinical Performance (NPS Specimens)	High Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) for each analyte. (Specific numerical thresholds not explicitly stated as acceptance criteria in the table but are implied by the nature of regulatory submissions for diagnostic tests.)	Table 2. R/ST Panel Performance Summary for NPS Specimens (Respiratory Menu):
Across prospective and archived studies, PPAs for individual viruses ranged from 96.3% (Respiratory syncytial virus) to 100% (Adenovirus, Human metapneumovirus, Influenza A A/H3, Influenza B, Chlamydia pneumoniae, Mycoplasma pneumoniae). NPAs for individual viruses ranged from 90.6% (Human rhinovirus/enterovirus) to 100% (Human metapneumovirus, Influenza A, Influenza A A/H1-2009, Influenza A A/H3, Influenza B, Bordetella parapertussis, Bordetella pertussis, Chlamydia pneumoniae, Mycoplasma pneumoniae). Overall high performance observed.
Clinical Performance (TS Specimens)	High Sensitivity / PPA and Specificity / NPA for each analyte. (Specific numerical thresholds not explicitly stated as acceptance criteria in the table but are implied by the nature of regulatory submissions for diagnostic tests.)	Table 3. R/ST Panel Performance Summary for TS Specimens (Sore Throat Menu):
Across prospective, archived, and contrived studies, Sensitivities/PPAs for individual viruses ranged from 81.8% (Adenovirus, archived) to 100% (multiple analytes). Specificities/NPAs for individual viruses ranged from 91.7% (Adenovirus, archived) to 100% (multiple analytes). Overall high performance observed, with some variations based on study type (e.g., contrived samples often showing 100% agreement due to controlled conditions). Culture was used as the reference method for Streptococcus dysgalactiae and Streptococcus pyogenes.
Sample Storage and Handling	"For the storage condition to be considered acceptable for each organism, 100% expected positive results were required to be observed in all samples tested. In addition, crossing point (Cp) values were evaluated for each relevant assay and trended across the conditions to assess analyte stability over time."	"Positive results were observed in 100% of all TSa samples tested at all conditions evaluated for all SPOTFIRE R/ST Panel analytes."
Conclusion: "The SPOTFIRE R/ST Panel provides accurate results when TS specimens are stored in Amies media for up to 4 hours at ambient temperature (15-25 °C), up to 3 days at refrigerated temperature (2-8 °C), and up to 30 days at frozen temperature (≤ -15 °C). Similar results were previously observed with NPS specimens stored in transport media."
Limit of Detection (LoD)	"The LoD for each SPOTFIRE R/ST Panel analyte was confirmed when positive results were reported in at least 95% (≥19/20) of replicates tested at the LoD (1× LoD), and fewer than 95% (≤18/20) of replicates tested at a concentration 10-fold below LoD (0.1× LoD). Equivalent detection of representative analytes in single analyte and multi-analyte samples was determined primarily based on concordance of positive or negative results at each test concentration."	"The LoD concentrations for the SPOTFIRE R/ST Panel analytes were confirmed...The panel accurately detected viruses and bacteria in samples contrived in either VTM or Amies media containing one or multiple organisms."
Conclusion: "The SPOTFIRE R/ST panel provides accurate detection results for all analytes in single or polymicrobial specimens when present at or above the LoD. No adverse effect on the analytical sensitivity of the SPOTFIRE R/ST Panel was observed when evaluating multi-analyte specimens."
Analytical Reactivity (Inclusivity)	"The assay reactivity of each isolate was confirmed if positive results were reported for the appropriate analyte in 3/3 or 4/5 replicates tested within 10× LoD. If positive results were reported in fewer than 4/5 replicates, additional testing was performed at 100× LoD or higher."	"Analytical reactivity testing demonstrated that the SPOTFIRE R/ST Panel can detect and accurately report results for a diverse collection of isolates from a variety of strains, serotypes, and genotypes of species collected over many years and from geographically distinct locations with few limitations." Specific limitations related to Streptococcus dysgalactiae and Streptococcus pyogenes were identified and noted in device labeling.
Analytical Specificity (Exclusivity)	"On-panel organisms were expected to have a positive result for the analyte being tested and negative results for all other analytes targeted by the panel. Off-panel organisms were expected to have negative results for all panel analytes, unless otherwise indicated."	"Six cross-reactivities were identified by empirical and/or in silico evaluations that are predicted to cause inaccurate test results...Five of the identified cross-reactivities are either due to reactivity between phylogenetic near-neighbors that are rarely observed in human populations or were further evaluated and found to not impact the panel's specificity relevant to the intended use." Specific limitations related to SARS-CoV-2, B. bronchiseptica, Bordetella species, influenza A viruses of swine origin, bovine/canine picornaviruses, and Chlamydia gallinacea were identified and noted in device labeling.
Interference (Interfering Substances)	"If an unexpected result or control failure was observed for one replicate of a sample containing a potentially interfering substance, the affected sample was retested in two additional pouches to determine if the failure was reproducible." Implied: accurate results should be maintained in the presence of interfering substances.	"Accurate results for the SPOTFIRE R/ST Panel were reported in the presence of a variety of potentially interfering substances...".
Conclusion: "The SPOTFIRE R/ST Panel provides accurate results in the presence of various potentially interfering substances." A warning about bleach was noted.
Near-LoD/Reproducibility	"For all organisms, a minimum of 90% agreement with the expected positive results (with 95% agreement desired) to demonstrate the reproducibility of positive results, and a minimum of 95% agreement with the expected negative results was required."	"For positive samples, agreement with the expected positive results (all systems/sites) was $\ge$ 95% for all analytes. The agreement with the expected negative results was 100% for all analytes. The total positive agreement reported for testing completed at BioFire and at clinical sites was nearly identical (99.1% (2052/2070) and 98.9% (1365/1380), respectively)..."
Conclusion: "The SPOTFIRE R/ST Panel provides accurate and reproducible analyte detection results over time and in actual use conditions when testing was performed over multiple days, by operators with differing skill levels, at different sites, using different SpotFire Systems and different reagent kit lots. ... support use of the SPOTFIRE R/ST Panel and SPOTFIRE System at sites that hold a CLIA Certificate of Waiver."
Matrix Validation	"Equivalent performance between the artificial and natural sample matrices was determined primarily based on agreement of positive and negative results at each test concentration. Artificial and natural matrices were considered equivalent if negative results were observed at the same or similar test concentration."	"Performance of the SPOTFIRE R/ST Panel was determined to be equivalent in natural and artificial NPS (nNS and aNS) and in natural and artificial throat swab (nTS and aTS) matrices for five representative panel analytes. In all cases, negative results were observed in artificial and natural matrices at the same or similar test concentrations."
Conclusion: "The results of this study demonstrated that the artificial NPS and artificial TS matrices were acceptable for use in analytical evaluation of SPOTFIRE R/ST Panel performance."
Transport Media Validation	"If the overall agreement was 100% when testing above the LoD and ≥95% when testing at the LoD, then the candidate medium was determined to be compatible. It was acceptable for the agreement to be less than 95% when testing below the LoD."	"Equivalent analyte detection was observed for all representative analytes when samples were prepared in each of the candidate media types (BD™ Universal Viral Transport, and Remel MicroTest™ M4RT® Multi-Microbe Media) compared to the control medium (CDC VTM)."
Conclusion: "The SPOTFIRE R/ST Panel demonstrated equivalent results when samples were prepared in Viral Transport Media, BD™ Universal Viral Transport, and Remel MicroTest™ M4RT® Multi-Microbe Media. These transport media are indicated in the product labeling as suitable for use with the SPOTFIRE R/ST Panel."
Sample Carry Over	"For positive samples, a positive result was expected for the analyte being tested and negative results were expected for all other analytes on the panel. Negative samples were expected to have a negative result for all analytes." Implied: No unexpected positive results due to carry-over.	"No unexpected positive results were observed in this study."
Conclusion: "This study demonstrated that sample-to-sample carry-over between samples containing high concentrations of organism and negative samples is unlikely to occur and that carry-over poses an acceptable risk to the accuracy of the SPOTFIRE R/ST Panel test results when testing is performed according to the instructions for use."

2. Sample Sizes Used for the Test Set and Data Provenance

The sample sizes vary by analyte and study type (prospective, archived, contrived).

Clinical Performance (Test Set):
- NPS Specimens (Respiratory Menu):
  - Prospective Data: The total number of NPS specimens tested across all viruses and bacteria is not explicitly stated as a single number but can be aggregated from the "Positive" and "Negative" counts for each analyte. For example, for Adenovirus, there were 33 positives and 1082 negatives, totaling 1115 prospective NPS specimens where Adenovirus was assessed. This appears to be the total number of clinical samples evaluated in the prospective study.
  - Archived Data: Similarly, for Adenovirus, there were 31 positives and 439 negatives, totaling 470 archived NPS specimens.
  - Contrived Data: Indicated as 0/0 for all NPS analytes, suggesting contrived samples were not used for clinical performance evaluation of NPS specimens.
- TS Specimens (Sore Throat Menu):
  - Prospective Data: For Adenovirus, 65 positives and 810 negatives (total 875). This seems to be the total number of clinical throat swab specimens assessed.
  - Archived Data: For Adenovirus, 11 positives and 48 negatives (total 59).
  - Contrived Data: For Adenovirus, 50 positives and 381 negatives (total 431). Contrived samples were used for TS clinical performance studies.
- Data Provenance: The document states "as tested by intended users," implying clinical sites. No specific country of origin is mentioned, but typically, these studies for FDA clearance involve sites within the US. The "Prospective" studies indicate prospective collection, while "Archived" refers to retrospective samples. "Contrived" samples are laboratory-prepared.
Analytical Performance (Test Set):
- Limit of Detection (LoD): At least 20 replicates (e.g., 19/20) tested at LoD and 10-fold below LoD for each analyte.
- Analytical Reactivity (Inclusivity): 3/3 or 4/5 replicates tested within 10x LoD for each isolate.
- Near-LoD/Reproducibility: Not explicitly stated but mentions "multiple days," "multiple operators," "three unique SPOTFIRE Systems," "three distinct clinical sites holding a CLIA waiver." The reported positive and negative agreement totals are 2070 (BioFire) and 1380 (clinical sites) tests.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and the Qualifications of Those Experts

The document does not specify the number of experts or their qualifications (e.g., radiologist with 10 years of experience) used to establish the ground truth. This is a common characteristic of in vitro diagnostic (IVD) submissions focusing on molecular diagnostic tests.

For molecular tests, the "ground truth" is typically established by comparator methods, often laboratory-developed tests (LDTs) or other cleared/validated molecular diagnostic assays (e.g., PCR followed by sequencing, or highly sensitive and specific reference PCR methods).
For bacterial culture (used for Streptococcus dysgalactiae and Streptococcus pyogenes), the ground truth is established by standard microbiological culture and identification techniques, performed by trained laboratory personnel.

4. Adjudication Method for the Test Set

The document does not describe a formal adjudication method (e.g., 2+1, 3+1) for the clinical test sets. This is expected given that the ground truth is established by laboratory reference methods (molecular or culture), which typically do not involve human reader adjudication in the same way imaging studies might. Any discrepancies between the investigational device and the reference method would be investigated by the manufacturer, rather than through an expert consensus adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, an MRMC comparative effectiveness study was not done. This type of study is primarily relevant for imaging-based AI devices where human readers interpret medical images, and the AI assists or augments their performance. The BIOFIRE SPOTFIRE R/ST Panel is a molecular diagnostic test where the output is an automated detection of nucleic acids, not an interpretation by a human reader that could be augmented by AI.

6. If a Standalone (i.e. Algorithm Only Without Human-in-the Loop Performance) Was Done

Yes, the performance data presented (Tables 2 and 3 for Clinical Performance, and Table 4 for Analytical Performance) represents the standalone performance of the BIOFIRE SPOTFIRE R/ST Panel, which includes the instrument and its automated software interpretation. The device itself is designed to provide automated results without human interpretive input for the detection of targets. The "as tested by intended users" for clinical performance indicates that the device was used in a realistic setting, but the performance metrics reflect the direct output of the system.

7. The Type of Ground Truth Used

The ground truth for the clinical performance evaluation was established using:

Comparator molecular assays or known specimen composition for most analytes (referred to as "molecular assays or known specimen composition were used as comparator methods" for PPA/NPA). This suggests a combination of validated PCR assays, and potentially sequencing for confirmation.
Culture for Streptococcus dysgalactiae (Group C/G Strep) and Streptococcus pyogenes (Group A Strep). This is explicitly stated: "Performance measures of sensitivity and specificity refer to the prospective and archived Streptococcus and archived Streptococcus analytes for which culture was used as the reference method."

For analytical studies, the ground truth was established by:

Known concentrations of organisms (e.g., viable or infectious units, nucleic acid copies/mL) for LoD and Inclusivity studies.
Defined panels of organisms or substances for Exclusivity and Interference studies.

8. The Sample Size for the Training Set

This document does not provide information on the training set size directly. The presented studies are for validation/testing of the device's performance. For molecular diagnostic assays like this, the 'training' of the algorithms (e.g., primer design, melt curve analysis interpretation) typically happens during the assay development phase, often using synthetic targets, cultured organisms, and preliminary clinical samples. However, this is not detailed in a 510(k) summary, which focuses on validation data against a defined product. The "software was verified and validated" statement implies that developmental data was used, but details on sample size for that specific phase are not provided in this regulatory summary.

9. How the Ground Truth for the Training Set Was Established

Since the training set details are not provided, the method for establishing its ground truth is also not explicitly stated in this document. However, based on typical IVD development practices:

Ground truth for assay development (which informs the 'training' of a molecular diagnostic system) would involve well-characterized positive and negative controls, reference strains, and potentially sequenced clinical isolates.
Molecular target sequences (in silico analysis)
Analytical dilution series where the exact concentration of the pathogen is known.
Samples confirmed by multiple, orthogonal laboratory methods.

The rigorous analytical and clinical studies described in the results section serve as the validation of the final trained/developed system.

Summary

Regulation Number and Section

§ 866.3981 Device to detect and identify nucleic acid targets in respiratory specimens from microbial agents that cause the SARS-CoV-2 respiratory infection and other microbial agents when in a multi-target test.

(a)
Identification. A device to detect and identify nucleic acid targets in respiratory specimens from microbial agents that cause the SARS-CoV-2 respiratory infection and other microbial agents when in a multi-target test is an in vitro diagnostic device intended for the detection and identification of SARS-CoV-2 and other microbial agents when in a multi-target test in human clinical respiratory specimens from patients suspected of respiratory infection who are at risk for exposure or who may have been exposed to these agents. The device is intended to aid in the diagnosis of respiratory infection in conjunction with other clinical, epidemiologic, and laboratory data or other risk factors.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The intended use in the labeling required under § 809.10 of this chapter must include a description of the following: Analytes and targets the device detects and identifies, the specimen types tested, the results provided to the user, the clinical indications for which the test is to be used, the specific intended population(s), the intended use locations including testing location(s) where the device is to be used (if applicable), and other conditions of use as appropriate.
(2) 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 specimen types claimed by this device; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.
(3) The labeling required under § 809.10(b) of this chapter must include:
(i) A detailed device description, including reagents, instruments, ancillary materials, all control elements, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens;
(ii) Detailed descriptions of the performance characteristics of the device for each specimen type claimed in the intended use based on analytical studies including the following, as applicable: Limit of Detection, inclusivity, cross-reactivity, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, precision, reproducibility, and clinical studies;
(iii) Detailed descriptions of the test procedure(s), the interpretation of test results for clinical specimens, and acceptance criteria for any quality control testing;
(iv) A warning statement that viral culture should not be attempted in cases of positive results for SARS-CoV-2 and/or any similar microbial agents unless a facility with an appropriate level of laboratory biosafety (
e.g., BSL 3 and BSL 3+, etc.) is available to receive and culture specimens; and(v) A prominent statement that device performance has not been established for specimens collected from individuals not identified in the intended use population (
e.g., when applicable, that device performance has not been established in individuals without signs or symptoms of respiratory infection).(vi) Limiting statements that indicate that:
(A) A negative test result does not preclude the possibility of infection;
(B) The test results should be interpreted in conjunction with other clinical and laboratory data available to the clinician;
(C) There is a risk of incorrect results due to the presence of nucleic acid sequence variants in the targeted pathogens;
(D) That positive and negative predictive values are highly dependent on prevalence;
(E) Accurate results are 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
(F) When applicable (
e.g., recommended by the Centers for Disease Control and Prevention, by current well-accepted clinical guidelines, or by published peer-reviewed literature), that the clinical performance may be affected by testing a specific clinical subpopulation or for a specific claimed specimen type.(4) Design verification and validation must include:
(i) Detailed documentation, including performance results, from a clinical study that includes prospective (sequential) samples for each claimed specimen type and, as appropriate, additional characterized clinical samples. The clinical study must be performed on a study population consistent with the intended use population and compare the device performance to results obtained using a comparator that FDA has determined is appropriate. Detailed documentation must include the clinical study protocol (including a predefined statistical analysis plan), study report, testing results, and results of all statistical analyses.
(ii) Risk analysis and documentation demonstrating how risk control measures are implemented to address device system hazards, such as Failure Modes Effects Analysis and/or Hazard Analysis. This documentation must include a detailed description of a protocol (including all procedures and methods) for the continuous monitoring, identification, and handling of genetic mutations and/or novel respiratory pathogen isolates or strains (
e.g., regular review of published literature and periodic in silico analysis of target sequences to detect possible mismatches). All results of this protocol, including any findings, must be documented and must include any additional data analysis that is requested by FDA in response to any performance concerns identified under this section or identified by FDA during routine evaluation. Additionally, if requested by FDA, these evaluations must be submitted to FDA for FDA review within 48 hours of the request. Results that are reasonably interpreted to support the conclusion that novel respiratory pathogen strains or isolates impact the stated expected performance of the device must be sent to FDA immediately.(iii) A detailed description of the identity, phylogenetic relationship, and other recognized characterization of the respiratory pathogen(s) that the device is designed to detect. In addition, detailed documentation describing how to interpret the device results and other measures that might be needed for a laboratory diagnosis of respiratory infection.
(iv) A detailed device description, including device components, 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, etc.), 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.(v) A detailed description of device software, including software applications and hardware-based devices that incorporate software. The detailed description must include documentation of verification, validation, and hazard analysis and risk assessment activities, including an assessment of the impact of threats and vulnerabilities on device functionality and end users/patients as part of cybersecurity review.
(vi) For devices intended for the detection and identification of microbial agents for which an FDA recommended reference panel is available, design verification and validation must include the performance results of an analytical study testing the FDA recommended reference panel of characterized samples. 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.
(vii) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiation between the Influenza A virus subtypes in human clinical specimens, the design verification and validation must include 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. 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.
(5) When applicable, performance results of the analytical study testing the FDA recommended reference panel described in paragraph (b)(4)(vi) of this section must be included in the device's labeling under § 809.10(b) of this chapter.
(6) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiation between the Influenza A virus subtypes in human clinical specimens in addition to detection of SARS-CoV-2 and similar microbial agents, the required labeling under § 809.10(b) 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.
(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 must include a clear interpretation instruction for all valid and invalid output combinations, and recommendations for any required followup 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 (
i.e., 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.(7) If one of the actions listed at section 564(b)(1)(A) through (D) of the Federal Food, Drug, and Cosmetic Act occurs with respect to an influenza viral strain, or if the Secretary of Health and Human Services 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 influenza viral samples in accordance with a standardized protocol considered and determined by FDA to be acceptable and appropriate.
(ii) Within 60 days from the date that FDA notifies manufacturers that characterized influenza 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 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 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 website, as well as the primary part of the manufacturer's website that discusses the device, must provide a prominently placed hyperlink to the website containing this information and must allow unrestricted viewing access.