(400 days)
The Cue COVID-19 Molecular Test is a nucleic acid amplification assay that is used with the Cue Health Monitoring System (Cue Cartridge Reader) for the rapid, qualitative detection of SARS-CoV-2 nucleic acid directly in anterior nasal swab specimens from individuals with signs and symptoms of COVID-19 (i.e., symptomatic).
A negative test result is presumptive, and it is recommended these results be confirmed by a labbased molecular SARS-CoV-2 assay if necessary for patient management. Negative results do not preclude SARS-CoV-2 infections and should not be used as the sole basis for treatment.
Positive results do not rule out co-infection with other respiratory pathogens.
This test is not a substitute for visits to a healthcare provider or appropriate follow-up and should not be used to determine any treatments without provider supervision.
This test is intended to be sold over-the-counter (OTC) for testing of individuals 18 years of age and older.
The device consists of the Cue Health Monitoring System (Cue Reader), the Cue COVID-19 Molecular Test Cartridge, and the Cue sample wand. Users must first download and install the Cue Health App onto their mobile smart device. Users then create an account (first time use) and pair the Cue Reader with the mobile smart device. Multiple profiles can be set up under each user account. The appropriate profile is selected and the user inserts the Cue COVID-19 Molecular Test Cartridge into the Cue Reader. The Cue COVID-19 Molecular Test Cartridge must warm up prior to initiating a run. The user collects an anterior nasal swab sample by swabbing both nares with the Cue sample wand and then inserts the Cue sample wand nasal sample into the port of the Cue COVID-19 Molecular Test Cartridge. The test will start as soon as the Cue Sample Wand is inserted into the Cue COVID-19 Molecular Test Cartridge and is completed in 20 minutes. The Cue Health App will show the Cue COVID-19 Molecular Test result when the test is complete. The result is saved in the Cue Account profile that was selected before the test started.
The provided text describes the evaluation of the Cue COVID-19 Molecular Test for an automatic Class III designation (De Novo request). The FDA's decision summary details the device's characteristics, analytical and clinical performance, and risk assessments.
Here's an analysis of the acceptance criteria and study that proves the device meets them:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state pre-defined acceptance criteria in a dedicated table. However, based on the VI Performance Characteristics and C Clinical Studies sections, the core performance metrics evaluated are:
| Metric | Acceptance Criteria (Implied) | Reported Device Performance |
|---|---|---|
| Analytical Performance | ||
| Precision (Agreement) | High agreement across variables (day, operator, lot) | Negative: 97% (93-99% CI) C20-80 (0.3xLoD): 90% (83-94% CI) C95 (1xLoD): 97% (93-99% CI) C100 (2.5xLoD): 100% (97-100% CI) |
| Cross-reactivity | No cross-reactivity with common respiratory pathogens | No cross-reactivity observed, except for SARS-CoV (2003 SARS outbreak) |
| Microbial Interference | No interference from common microorganisms on SARS-CoV-2 detection | No interference observed |
| Interfering Substances | No interference from common nasal substances | No interference observed, except for Saline Nasal Spray, Chloroseptic lozenge, and Rhinallergy (false positives observed in some negative samples, limiting statements added to labeling) |
| Limit of Detection (LoD) | Detect SARS-CoV-2 at a low concentration (≥ 95% detection) | 20 copies/wand (established); 7.7x10^6 IU/mL (WHO International Standard) |
| Inclusivity (Variant Detection) | Detect various SARS-CoV-2 strains | 100% detection at 3xLoD for tested strains (including Omicron BA.1, BA.1.1, BA.2, BA.5). In silico analysis showed 98.853% of US circulating strains had no mismatches, 0.738% risk level 1, 0.415% risk level 2. |
| Carry-Over | No carry-over between samples | No evidence of carry-over observed (100% expected results) |
| Clinical Performance | ||
| Positive Percent Agreement (PPA) | High agreement with comparator for positive samples | 92.9% (130/140) (95% CI: 87.4% - 96.1%) |
| Negative Percent Agreement (NPA) | High agreement with comparator for negative samples | 98.7% (752/762) (95% CI: 97.6% - 99.3%) |
| Usability/User Comprehension | Lay users can successfully operate and comprehend results | 98% (93/95) successfully completed testing. Questionnaire assessed comprehension. |
| Failsafe Features | Device features designed to minimize false results from user error/environmental factors should function as intended | Tested and mostly successful in mitigating risks (e.g., cancelled tests for improper wand insertion, low battery, expired cartridges, tilt; some false results noted in extreme environmental stress studies but mitigated by labeling) |
Note on Acceptance Criteria: The document does not explicitly state numerical acceptance thresholds for all analytical performance metrics. For example, for precision, it simply presents the results. For LoD, the criterion "≥ 95% of the replicates tested are positive" is explicitly stated. For clinical performance, while specific targets are not given as "acceptance criteria," the reported PPA and NPA are high and fall within confidence intervals typical for FDA-authorized molecular tests for diagnostic purposes. The FDA's granting of the De Novo request implies that the performance met their internal criteria for Class II designation.
2. Sample Size Used for the Test Set and Data Provenance
- Clinical Test Set Sample Size: 902 evaluable subjects.
- Data Provenance:
- Country of Origin: Not explicitly stated, but the study refers to SARS-CoV-2 variants circulating in the "United States" for in silico analysis, suggesting the clinical study likely involved US-based subjects/sites. The manufacturer, "Cue Health Inc.", is a US company.
- Retrospective or Prospective: The clinical study was prospective. It states, "A prospective all-comer study enrolled subjects at 13 sites, from December 2020 - February 2021 and November 2021- February 2022 to evaluate the clinical performance..."
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The document does not specify the number or qualifications of experts directly establishing the ground truth for the clinical test set. Instead, the ground truth was established by a "consensus comparator (agreement between at least two FDA Emergency Use Authorized (EUA) molecular tests for SARS-CoV-2)". This implies that these FDA EUA molecular tests served as the reference standard, rather than human experts adjudicating results.
For analytical performance studies (e.g., precision, LoD, cross-reactivity), the ground truth was established by carefully prepared samples with known concentrations of analytes (e.g., inactivated SARS-CoV-2, specific bacteria/viruses).
4. Adjudication Method for the Test Set
For the clinical test set, the adjudication method was a consensus comparator: "agreement between at least two FDA Emergency Use Authorized (EUA) molecular tests for SARS-CoV-2".
For analytical performance studies, the ground truth was based on the known composition and concentration of the spiked samples, not expert adjudication.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not conducted for the Cue COVID-19 Molecular Test. This device is an automated molecular test, not an AI intended to assist human readers in interpreting images or data. Therefore, a study to measure how much human readers improve with AI vs. without AI assistance is not applicable. The focus is on the standalone performance of the device and its usability by lay users.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study
Yes, the primary evaluation of the Cue COVID-19 Molecular Test is effectively a standalone (algorithm only without human-in-the-loop performance) study, though the "human-in-the-loop" here refers to the lay user operating the device and collecting the sample, rather than interpreting a complex output.
- The
Analytical Performancesection directly assesses the device's ability to detect SARS-CoV-2 nucleic acid independently (e.g., LoD, cross-reactivity, inclusivity). - The
Clinical Studiessection compares the device's output (positive/negative) against a consensus comparator, reflecting its standalone diagnostic performance in a real-world setting with lay users performing the test steps but the device providing the result. The device itself interprets the signal and provides a qualitative result.
7. The Type of Ground Truth Used
- Clinical Study Ground Truth: Consensus comparator results from "at least two FDA Emergency Use Authorized (EUA) molecular tests for SARS-CoV-2." This is a strong, highly accurate reference standard for SARS-CoV-2 detection.
- Analytical Performance Study Ground Truth: Known concentrations of inactivated SARS-CoV-2 and other microorganisms/substances spiked into clinical nasal matrix or onto sample wands. This is a controlled, objective ground truth based on laboratory preparations.
8. The Sample Size for the Training Set
The document does not report specific sample sizes for a 'training set' for the Cue COVID-19 Molecular Test. This is because the described studies are verification and validation studies for a new device (a molecular test), not for an AI/ML algorithm that typically requires distinct training, validation, and test datasets. The "development" or "training" of the underlying assay chemistry and instrument logic would have occurred prior to these outlined performance studies. The studies described here are to prove the device meets acceptance criteria, which typically uses a separate, held-out test set, not a training set.
9. How the Ground Truth for the Training Set Was Established
As noted above, the document does not describe a distinct 'training set' or the establishment of its ground truth, consistent with the nature of a molecular diagnostic device evaluation rather than an AI/ML algorithm. The ground truth for all performance evaluations relies on the methods described in point 7 (consensus comparator for clinical, known spiked concentrations for analytical).
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EVALUATION OF AUTOMATIC CLASS III DESIGNATION FOR Cue COVID-19 Molecular Test DECISION SUMMARY
I Background Information:
A De Novo Number
B Applicant
Cue Health Inc.
C Proprietary and Established Names
Cue COVID-19 Molecular Test
D Regulatory Information
| ProductCode(s) | Classification | RegulationSection | Panel |
|---|---|---|---|
| QWB | II | 21 CFR 866.3984 | MI - Microbiology |
Submission/Device Overview: II
A Purpose for Submission:
De Novo request for evaluation of automatic class III designation for the Cue COVID-19 Molecular Test.
B Measurand:
SARS-Coronavirus 2 (SARS-CoV-2) nucleic acid
C Type of Test:
Isothermal nucleic acid amplification test
III Indications for Use:
A Indication(s) for Use:
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The Cue COVID-19 Molecular Test is a nucleic acid amplification assay that is used with the Cue Health Monitoring System (Cue Cartridge Reader) for the rapid, qualitative detection of SARS-CoV-2 nucleic acid directly in anterior nasal swab specimens from individuals with signs and symptoms of COVID-19 (i.e., symptomatic).
A negative test result is presumptive, and it is recommended these results be confirmed by a labbased molecular SARS-CoV-2 assay if necessary for patient management. Negative results do not preclude SARS-CoV-2 infections and should not be used as the sole basis for treatment.
Positive results do not rule out co-infection with other respiratory pathogens.
This test is not a substitute for visits to a healthcare provider or appropriate follow-up and should not be used to determine any treatments without provider supervision.
This test is intended to be sold over-the-counter (OTC) for testing of individuals 18 years of age and older.
B Special Conditions for Use Statement(s):
OTC - Over The Counter
C Special Instrument Requirements:
A mobile smart device with wifi access and the Cue Health Monitoring System (Cue Reader).
IV Device/System Characteristics:
A Device Description:
The device consists of the Cue Health Monitoring System (Cue Reader), the Cue COVID-19 Molecular Test Cartridge, and the Cue sample wand. Users must first download and install the Cue Health App onto their mobile smart device. Users then create an account (first time use) and pair the Cue Reader with the mobile smart device. Multiple profiles can be set up under each user account. The appropriate profile is selected and the user inserts the Cue COVID-19 Molecular Test Cartridge into the Cue Reader. The Cue COVID-19 Molecular Test Cartridge must warm up prior to initiating a run. The user collects an anterior nasal swab sample by swabbing both nares with the Cue sample wand and then inserts the Cue sample wand nasal sample into the port of the Cue COVID-19 Molecular Test Cartridge. The test will start as soon as the Cue Sample Wand is inserted into the Cue COVID-19 Molecular Test Cartridge and is completed in 20 minutes. The Cue Health App will show the Cue COVID-19 Molecular Test result when the test is complete. The result is saved in the Cue Account profile that was selected before the test started.
B Principle of Operation
The Cue COVID-19 Molecular Test Cartridge utilizes isothermal nucleic acid amplification technology for the qualitative detection of SARS-CoV-2 nucleic acids. This test is a molecular nucleic acid amplification test (NAAT) that detects the nucleic acid of SARS-CoV-2 using a molecular amplification reaction. The SARS-CoV-2 target primers amplify a region of the
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nucleocapsid (N) gene. The SARS-CoV-2 target forward primer is conjugated to an affinity tag. RNase P serves as the internal control. The RNase P forward primer is conjugated to a different affinity tag. Both SARS-CoV-2 target and RNase P reverse primers are conjugated to an enzyme. Both the SARS-CoV-2 target and RNase P probes bind to the middle-region of the target amplicon. Following target amplicons the amplicons are bound to a functionalized electrode (one for SARS-CoV-2 and one fore RNase P) via the affinity tag conjugated to the forward primer. The enzyme-bound to the reverse primer then catalyzes a redox reaction. The current flow from the electrodes provides a semi-quantitative nanoampere measurement that is converted to a positive or negative result (based on a pre-determined cutoff).
The RNase P internal control has been designed to control for presence of human cellular. material in the sample and proper assay execution including sample lysis, inhibition, amplification, and assay reagent function for each critical step. If RNase P is not detected, the Cue COVID-19 Molecular Test will return an "Invalid" result.
When the user inserts the Cue sample wand with anterior nasal sample into the cartridge, the test automatically begins. Heating, mixing, amplification, and detection take place within the cartridge.
C Instrument Description Information
-
- Instrument Name: Cue Health Monitoring System (Cue Reader).
-
- Specimen Identification: Anterior Nasal Swabs.
-
- Specimen Sampling and Handling: Once the sample has been collected, the Cue sample wand is immediately inserted directly into the Cue COVID-19 Molecular Test Cartridge.
-
- Calibration: Not Applicable.
-
- Quality Control: Internal Control.
V Standards/Guidance Documents Referenced:
| Document Number | Title | Publishing Organization |
|---|---|---|
| EP17-A2 | Evaluation of Detection Capability for Clinical LaboratoryMeasurement Procedures, 2nd Edition | CLSI |
| EP25 | Evaluation of Stability of In Vitro Diagnostic Reagents | CLSI |
| N/A | Content of Premarket Submissions for Software Contained inMedical Devices | FDA |
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| Document Number | Title | Publishing Organization |
|---|---|---|
| N/A | Content of Premarket Submissions for Management ofCybersecurity in Medical Devices | FDA |
| ISO 10993-1:2018 | Biological evaluation of medical devices - Part 1: Evaluation andtesting within a risk management process | ANSI AAMI ISO |
| ISO 14971:2019 | Medical devices - Applications of risk management to medicaldevices | ANSI AAMI ISO |
| IEC 62133:2012 | Secondary cells and batteries containing alkaline or other non-acidelectrolytes - Safety requirements for portable sealed secondarycells, and for batteries made from them, for use in portableapplications | IEC |
| IEC 60601-1-2:2014 | Medical electrical equipment -- Part 1-2: General requirements forbasic safety and essential performance -- Collateral Standard:Electromagnetic disturbances -- Requirements and tests | ANSI AAMI IEC |
VI Performance Characteristics:
A. Analytical Performance
1. Precision:
A precision study was conducted to assess the total variability of the Cue COVID-19 Molecular Test across testing days, operators, and Cue COVID-19 Molecular Test cartridge lots. The testing panel was with inactivated SARS-CoV-2 (isolate USA-WA1/2020) diluted into clinical nasal matrix and then spiked onto Cue sample wands. The testing panel consisted of four members: (1) Negative (no analyte); (2) C20.80 (0.3xLoD); (3) C95 (1xLoD); and (4) C100 (2.5xLoD), Cue COVID-19 Molecular Test cartridge lots were tested by two operators each across twelve non-consecutive days, each running two replicates per day (3 lots × 2 operators/lot × 12 days/operator × 2 replicates/day) for a total of 144 observations per panel member. A total of 60 Cue readers were used in this study. The results are presented in Table 1.
| Percent agreement with expected results (n/N) (95% Confidence Interval) | |||||
|---|---|---|---|---|---|
| Lot | Operator | Negative | C20-80 | C95 | C100 |
| 1 | Operator 1 | 100% (24/24) (86 -100%) | 96% (23/24) (79 -100%)a | 92% (22/24) (73 -99%) | 100% (24/24) (86% -100%) |
| Operator 2 | 96% (23/24) (79 -100%)b | 83% (20/24) (63 -95%) | 100% (24/24) (86 -100%) | 100% (24/24) (86% -100%) | |
| Overall | 98% (47/48) (89% -100%) | 90% (43/48) (77% -97%) | 96% (46/48) (79% -100%) | 100% (48/48) (93% -100%) | |
| 2 | Operator 1 | 96% (23/24) (79 -100%) | 96% (23/24) (79 -100%) | 96% (23/24) (79 -100%)c | 100% (24/24) (86% -100%) |
| Operator 2 | 100% (24/24) (86 -100%) | 92% (22/24) (73 -99%) | 100% (24/24) (86 -100%)d | 100% (24/24) (86% -100%) | |
| Overall | 98% (47/48) (89% -100%) | 94% (44/48) (83% -99%) | 98% (47/48) (89% -100%) | 100% (48/48) (93% -100%) |
| Table 1. Result of the Precision for the Cue COVID-19 Molecular Test. | ||||||
|---|---|---|---|---|---|---|
| ----------------------------------------------------------------------- | -- | -- | -- | -- | -- | -- |
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| Lot | Operator | Percent agreement with expected results (n/N) (95% Confidence Interval) | |||
|---|---|---|---|---|---|
| Negative | C20-80 | C95 | C100 | ||
| Operator 1 | 100% (24/24) (86 -100%) | 79% (19/24) (58 -93%) | 100% (24/24) (86 -100%) | 100% (24/24) (86% -100%) | |
| Operator 2 | 92% (22/24) (73 -99%) | 92% (22/24) (73 -99%) | 96% (23/24) (79 -100%) | 100% (24/24) (86% -100%) | |
| 3 | Overall | 96% (46/48) (79% -100%) | 85% (41/48) (72% -94%) | 98% (47/48) (89% -100%) | 100% (48/48) (93% -100%) |
| Overall | 97% (140/144)(93% - 99%) | 90% (129/144)(83% - 94%) | 97% (140/144)(93% - 99%) | 100% (144/144)(97% - 100%) |
"One cancelled test was repeated.
b One invalid result and one cancelled test were repeated.
One invalid result was repeated.
One cancelled test was repeated.
2. Linearity:
This study is not applicable as this test device is a qualitative assay.
3. Analytical Specificity/Interference:
- a. Cross-reactivity
The cross-reactivity was evaluated by testing various bacteria (23), viruses (22), fungi (3), and pooled nasal wash with the Cue COVID-19 Molecular Test cartridge. Each organism or virus was tested by spiking of the microorganism onto a Cue sample wand. The crossreactivity was evaluated by the number of SARS-CoV-2 positive results against the expected negative results. The results, presented in Table 2, show that no cross reactivity was observed at the concentrations tested. except for SARS-CoV (coronavirus from 2003 SARS outbreak).
| Organism | Concentration | SARS-CoV-2positive/replicates tested |
|---|---|---|
| Bordetella pertussis | $5.95 \times 10^7$ CFU/wand | 0/3 |
| Chlamydia pneumoniae | $7.35 \times 10^5$ CFU/wand | 0/3 |
| Corynebacterium diphtheriae | $2.69 \times 10^7$ CFU/wand | 0/3 |
| Escherichia coli | $5.45 \times 10^6$ CFU/wand | 0/3c |
| Haemophilus influenzae | $3.49 \times 10^6$ CFU/wand | 0/3 |
| Lactobacillus plantarum | $1.57 \times 10^7$ CFU/wand | 0/3 |
| Legionella pneumophila | $9.55 \times 10^7$ CFU/wand | 0/3c |
| Moraxella/Branhamella catarrhalis | $1.64 \times 10^5$ CFU/wand | 0/3 |
| Mycobacterium tuberculosis | $1.15 \times 10^6$ CFU/wand | 0/3c |
| Mycoplasma pneumoniae | $1.35 \times 10^6$ CFU/wand | 0/3 |
| Neisseria meningitides | $3.56 \times 10^6$ CCU/wand | 0/3 |
| Organism | Concentration | SARS-CoV-2positive/replicates tested |
| Neisseria subflava | 1.64 × 107 CFU/wand | 0/3 |
| Pseudomonas aeruginosa | 8.70 × 106 CFU/wand | 0/3 |
| Staphylococcus aureus | 4.18 × 107 CFU/wand | 0/3 |
| Staphylococcus epidermidis | 3.85 × 107 CFU/wand | 0/20b,c |
| Streptococcus pneumonia | 6.70 × 106 CFU/wand | 0/3 |
| Streptococcus salivarius | 2.26 × 106 CFU/wand | 0/3 |
| Streptococcus pyogenes | 9.55 × 106 CFU/wand | 0/3 |
| Adenovirus Type 1 | 1.55 × 106 TCID50/wand | 0/20 |
| Adenovirus Type 7 | 2.29 × 104 TCID50/wand | 0/3 |
| Enterovirus Type 70 | 8.00 × 104 TCID50/wand | 0/3 |
| Epstein Barr Virus | 3.93 × 105 copies/wand | 0/3 |
| Human Coronavirus 229E | 1.26 × 103 TCID50/wand | 0/3 |
| Human Coronavirus 0C43 | 5.25 × 103 TCID50/wand | 0/3c |
| Human Coronavirus HKU1 | 9.25 × 105 copies/wand | 0/3 |
| Human Coronavirus NL63 | 5.50 × 103 TCID50/wand | 0/3a |
| MERS-Coronavirus (Inactivated) | 2.09 × 103 TCID50/wand | 0/3 |
| Human Cytomegalovirus | 2.09 × 103 TCID50/wand | 0/3 |
| Human Metapneumovirus | 5.85 × 102 TCID50/wand | 0/3 |
| Measles | 8.00 × 102 TCID50/wand | 0/3 |
| Mumps | 4.78 × 104 TCID50/wand | 0/3 |
| Parainfluenza 1 | 6.30 × 103 TCID50/wand | 0/3 |
| Parainfluenza 2 | 2.09 × 103 TCID50/wand | 0/3 |
| Parainfluenza 3 | 4.26 × 105 TCID50/wand | 0/3 |
| Parainfluenza 4 | 2.50 × 104 TCID50/wand | 0/3 |
| Rhinovirus type 1 A | 7.55 × 103 TCID50/wand | 0/20 |
| Respiratory Syncytial Virus B | 4.78 × 104 TCID50/wand | 0/3 |
| Candida albicans | 2.51 × 106 CFU/wand | 0/3 |
| Influenza Type A | 4.80 × 104 TCID50/wand | 0/3 |
| Influenza Type B | 1.00 × 105 TCID50/wand | 0/3 |
| Mycoplasma genitalium | 7.19 × 106 copies/wand | 0/3 |
| Aspergillus fumigatus | 3.40 × 105 CFU/wand | 0/3 |
| Organism | Concentration | SARS-CoV-2positive/replicates tested |
| Aspergillus flavus | $1.82 \times 10^5$ CFU/wand | 0/3 |
| Fusobacterium necrophorum | $4.33 \times 10^6$ CFU/wand | 0/3 |
| Bordetella parapertussis (E595) | $4.69 \times 10^7$ CFU/wand | 0/3 |
| Bordetella parapertussis (A747) | $3.44 \times 10^7$ CFU/wand | 0/3 |
| Pooled human nasal wash | (b)(4) | 0/3 |
| P.jiroveci-S.cerevisiae Recombinant | (b)(4) CFU/wand | 0/3 |
| SARS Coronavirus (SARS-CoV) | 10 fold dilution of stock with Ctvalues from 25-28 | 1/3 |
Table 2. Results of Cross-Reactivity Testing for the Cue COVID-19 Molecular Test.
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10 One cancelled test was repeated.
b Two cancelled tests were repeated.
One invalid result was repeated.
CCU = color changing units
Additionally, cross-reactivity was assessed by in silico analysis of the test primers/probe sequences against the genome sequences of the microorganisms listed in the table above. Except for SARS-CoV (coronavirus from 2003 SARS outbreak), none of the test (0)|4) primer/probe sequences showed to any of the microorganisms analyzed.
b. Microbial Interference
Microbial interference was evaluated by testing various bacteria (22), viruses (21), and fungi (3) with the Cue COVID-19 Molecular Test cartridge. Each organism or virus was prepared, at the concentrations listed in Table 3, with inactivated SARS-CoV-2 (isolate USA-WA1/2020) at 3xLoD and then spiked onto Cue sample wands. The results, presented in Table 3, show that no interference was observed at the concentrations tested.
Table 3. Results of Microbial Interference Testing for the Cue COVID-19 Molecular Test.
| Organism | Concentration | SARS-CoV-2positive/ replicatestested |
|---|---|---|
| Bordetella pertussis | (b)(4) × 107 CFU/wand | 3/3 |
| Chlamydia pneumoniae | 7.35 × 105 CFU/wand | 3/3 |
| Corynebacterium diphtheriae | 2.69 × 107 CFU/wand | 3/3 |
| Escherichia coli | 1.36 × 106 CFU/wand | 3/3 |
| Haemophilus influenzae | 3.49 × 106 CFU/wand | 3/3 |
| Lactobacillus plantarum | 1.57 × 107 CFU/wand | 3/3 |
| Legionella pneumophila | 9.55 × 107 CFU/wand | 3/3 |
| Organism | Concentration | SARS-CoV-2positive/ replicatestested |
| Moraxella/Branhamella catarrhalis | 1.64 × 105 CFU/wand | 3/3 |
| Mycobacterium tuberculosis | 1.15 × 106 CFU/wand | 3/3 |
| Mycoplasma pneumoniae | 1.35 × 106 CFU/wand | 3/3a |
| Neisseria meningitides | 3.56 × 106 CFU/wand | 3/3 |
| Neisseria subflava | 1.64 × 107 CFU/wand | 3/3 |
| Pseudomonas aeruginosa | 8.70 × 106 CFU/wand | 3/3 |
| Staphylococcus aureus | 4.18 × 107 CFU/wand | 3/3a |
| Staphylococcus epidermidis | 3.85 × 107 CFU/wand | 3/3 |
| Streptococcus pneumonia | 3.35 × 106 CFU/wand | 3/3 |
| Streptococcus salivarius | 2.26 × 106 CFU/wand | 3/3 |
| Streptococcus pyogenes | 9.55 × 106 CFU/wand | 3/3 |
| Adenovirus Type 1 | 1.55 × 106 TCID50/wand | 3/3 |
| Adenovirus Type 7 | 2.29 × 104 TCID50/wand | 3/3 |
| Enterovirus Type 70 | 8.00 × 104 TCID50/wand | 3/3b |
| Epstein Barr Virus | 3.93 × 105 copies/wand | 3/3 |
| Human Coronavirus 229E | 7.05 × 102 TCID50/wand | 3/3 |
| Human Coronavirus 0C43 | 5.25 × 103 TCID50/wand | 3/3 |
| Human Coronavirus HKU1 | 9.25 × 105 copies/wand | 4/4a,c |
| Human Coronavirus NL63 | 2.75 × 103 copies/wand | 3/3a |
| MERS Coronavirus | 2.09 × 103 TCID50/wand | 3/3 |
| Human Cytomegalovirus | 2.09 × 103 TCID50/wand | 3/3 |
| Human Metapneumovirus | 5.85 × 102 TCID50/wand | 3/3 |
| Measles | 8.00 × 102 TCID50/wand | 3/3 |
| Organism | Concentration | SARS-CoV-2positive/ replicatetested |
| Mumps | 4.78 × $10^4$ TCID50/wand | 3/3 |
| Parainfluenza 1 | 6.30 × $10^3$ TCID50/wand | 3/3 |
| Parainfluenza 2 | 2.09 × $10^3$ TCID50/wand | 3/3 |
| Parainfluenza 3 | 2.13 × $10^5$ TCID50/wand | 3/3 |
| Parainfluenza 4 | 2.50 × $10^4$ TCID50/wand | 3/3ª |
| Rhinovirus type 1A | 7.55 × $10^3$ TCID50/wand | 3/3 |
| Respiratory Syncytial Virus B | 4.78 × $10^4$ TCID50/wand | 3/3 |
| Candida albicans | 2.51 × $10^6$ CFU/wand | 3/3 |
| Influenza Type A | 4.80 × $10^4$ TCID50/wand | 3/3 |
| Influenza Type B | 6.50 × $10^3$ TCID50/wand | 3/3 |
| Mycoplasma genitalium | 7.19 × $10^6$ copies/wand | 3/3 |
| Aspergillus fumigatus | 3.40 × $10^5$ CFU/wand | 3/3 |
| Aspergillus flavus | 1.82 × $10^5$ CFU/wand | 3/3 |
| Fusobacterium necrophorum | 4.33 × $10^6$ CFU/wand | 3/3 |
| Bordetella parapertussis (E595) | 4.69 × $10^7$ CFU/wand | 3/3 |
| Bordetella parapertussis (A747) | 3.44 × $10^7$ CFU/wand | 3/3 |
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a One cancelled test was repeated.
b One invalid result was repeated.
One additional test was run.
b. Interfering substances.
An interfering substances study was conducted to assess the performance of the Cue COVID-19 Molecular Test in the presence of medically and/or physiologically relevant concentrations of potentially interfering substances that may be present in anterior nasal swab specimens. Each potentially interfering substance was prepared, at the concentrations listed in Table 4, in negative clinical nasal matrix and in the presence of inactivated SARS-CoV-2 (isolate USA-WA1/2020) at 3xLoD. Samples were spiked onto Cue sample wands. The results, presented in Table 4, show that no interference was observed at the concentrations tested, except for false positive results in the presence of Saline Nasal Spray at 2.0 uL/wand, Chloroseptic lozenge at 2.0 uL/wand, and Rhinallergy 2.0 uL/wand. Limiting statements for these substances have been added to the labeling.
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| Substance | Concentration | SARS-CoV-2 positive/ replicatestested | |
|---|---|---|---|
| Negative NasalMatrix | 3xLoD SARS-CoV-2 | ||
| Afrin | 2.0 µL/wand | 0/6 | 3/3 |
| Saline Nasal Spray | 2.0 µL/wand | 1/12 | 3/3 |
| Zicam Allergy Relief | 2.0 µL/wand | 0/3a | 3/3 |
| Chloroseptic Max | 2.0 µL/wand | 0/6 | 3/3 |
| Neo-Synephrine | 2.0 µL/wand | 0/6 | 3/3a |
| Nasacort | 0.4 ng/wand | 0/6a | 3/3 |
| Flonase/Fluticasone | 0.4 ng/wand | 0/6 | 3/3 |
| Flunisolide | 0.4 ng/wand | 0/6 | 3/3 |
| Dexamethasone | 5.0 ng/wand | 0/6 | 3/3 |
| Beclomethasone | 0.68 ng/wand | 0/6 | 3/3a |
| Mometasone | 0.4 ng/wand | 0/6a | 3/3 |
| Budesonide | 0.5 ng/wand | 0/6 | 3/3a |
| Chloroseptic Lozenge | 2mg/wand | 1/12 | 3/3 |
| Zanamivir (Relenza) | 3.0 ng/wand | 0/6 | 3/3 |
| Tamiflu (Oseltamivir phosphate) | 0.1ng/wand | 0/6 | 3/3 |
| Xofluza (baloxavir marboixil) | 0.1ng/wand | 0/6 | 3/3 |
| Mupirocin | 100 ng/wand | 0/6 | 3/3 |
| Tobramycin | 25ng/wand | 0/6 | 3/3 |
| Galphimia Glauca | 2mg/wand | 0/6 | 3/3 |
| Rhinallergy | 2mg/wand | 1/12 | 3/3 |
| Biotin | 0.035 ug/wand | 0/6 | 3/3 |
| Mucin | 0.5mg/wand | 0/3 | 3/3 |
| Whole Blood | 0.5µL/wand | 0/3 | 3/3 |
Table 4. Results of Interfering Substances Testing for the CoVID-19 Molecular Test.
a One cancelled test was repeated.
N/A = Positive Panel member was not tested at that substance's concentration.
4. Assay Reportable Range:
This section is not applicable as this test device is a qualitative assay.
5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods): a. Unopened Kit Stability
A multi-lot reagent stability study was conducted to establish the shelf-life of the Cue COVID-19 Molecular Test cartridge. Cartridges were stored at temperatures up to 25ºC. Three different lots were tested at monthly intervals for up to 9 months. Cartridge stability was evaluated by the agreement with the negative or positive results expected for the testing panel. The testing panel consisted of negative clinical nasal matrix spiked onto Cue sample wands or inactivated SARS-CoV-2 diluted into clinical nasal matrix and then spiked onto
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Cue sample wands at 3xLoD. Ten negative and 10 positive Cue sample wands were tested with each lot at each storage duration. All tested negative and positive Cue sample wands produced 100% agreement with the expected results. The study results demonstrated the stability Cue COVID-19 Molecular test cartridge for up to eight months when stored at 22℃.
b. Shipping Stability
A reagent stability study was conducted to establish the stability of the Cue COVID-19 Molecular Test cartridge under conditions representing the extreme temperatures and durations anticipated during shipping. Cartridges underwent the summer profile ( 1964) between 22°C and 40°C) for a total of | mirectly followed by the winter profile (10 (p)(4) between -10℃ and 18℃) for a total of . Finally, cartridges were held at controlled temperature and humidity for [ (0(4) | and then subjected to a series of vibrational and shock simulations. Cartridge stability was evaluated by the agreement with the negative or positive results expected for the testing panel. The testing panel consisted of negative clinical nasal matrix spiked onto Cue sample wands or inactivated SARS-CoV-2 diluted into clinical nasal matrix and then spiked onto Cue sample wands at 3xLoD. @ negative and [ ] positive Cue sample wands were tested with each lot at each storage duration. All tested negative and positive Cue sample wands produced 100% agreement with the expected results. The study results demonstrate the stability of the Cue COVID-19 Molecular test cartridge under anticipated shipping conditions.
6. Detection Limit:
a. Limit of Detection
An analytical sensitivity study was conducted to determine the limit of detection (LoD) for the Cue COVID-19 Molecular Test cartridge. The LoD is defined as the lowest concentration (copies per Cue sample wand, copies/wand) at which ≥ 95% of the replicates tested are positive. A preliminary LoD was established by testing four concentrations of inactivated SARS-CoV-2 (isolate USA-WA1/2020) diluted into clinical nasal matrix and spiked onto Cue sample wands. Forty-eight replicates were tested at each dilution by two operators over three days in two lots of the Cue COVID-19 Molecular Test cartridges. The preliminary LoD, established at 20 copies/wand, was confirmed by testing 20 additional replicates with each lot of Cue COVID-19 Molecular Test cartridges at 20 copies/wand and 10 copies/wand. The LoD for the Cue COVID-19 Molecular Test has been established at 20 copies/wand. The results of the LoD study are summarized in the Tables 5 and 6.
| Copies/wand | Lot | % Detection (n/N) |
|---|---|---|
| 27251K | 100% (24/24) | |
| (b)(4) | 27140B | 100% (24/24)a |
| 27251K | 100% (24/24) | |
| 60 | 27140B | 91.7% (22/24)b |
| 27251K | 95.8% (23/24) | |
| 20 | 27140B | 95.8% (23/24) |
| 27251K | 66.7% (16/24) | |
| (b)(4) | 27140B | 62.5% (15/24) |
Table 5. Results of the Preliminary LoD for the Cue COVID-19 Molecular Test.
" two cancelled replicates and one invalid replicate were retested.
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b one cancelled replicate was retested.
| Copies/wand | Lot | Detection |
|---|---|---|
| 27251K | 95% (19/20) | |
| 20 | 27140B | 100%(24/24) |
| 27251K | 40% (8/20) | |
| 10 | 27140B | 60% (12/20) |
Table 6. Results of the Confirmatory LoD for the Cue COVID-19 Molecular Test.
8 one cancelled replicates and one invalid replicate were retested.
b one invalid replicate was retested.
c one cancelled replicate was retested.
b. WHO Testing Panel.
The analytical sensitivity was also evaluated using the First WHO International Standard for SARS-CoV-2 RNA. The analytical sensitivity for the Cue COVID-19 Molecular Test is established at 7.7×106 IU/mL using the First WHO International Standard for SARS-CoV-2 RNA.
7. Inclusivity
An analytical reactivity study was conducted to evaluate the ability of the Cue COVID-19 Molecular Test to detect multiple SARS-CoV-2 strains that are temporally and geographically diverse. Testing was performed on different strains of inactivated virus diluted into clinical nasal matrix and spiked onto Cue sample wands at 3xLoD. The results, presented in Table 7, show that strains were detected at 100% at the target concentrations.
Table 7. Results of Analytical Reactivity Testing for the Cue COVID-19 Molecular Test.
| Strain | Concentration(copies/wand) | Percent Detected (n/3) |
|---|---|---|
| UK B.1.1.7 | 60 | 100% (3/3)a |
| Japan/Brazil P.1 | 60 | 100% (3/3) |
| Japan/Brazil P.1 | 60 | 100% (3/3) |
| South Africa B.1.351 | 60 | 100% (3/3) |
| US NY B1.526 | 60 | 100% (3/3) |
| US NY B1.526 | 60 | 100% (3/3) |
| India B.1.617.1 | 60 | 100% (3/3) |
| India B.1.617.2 | 60 | 100% (3/3) |
| India B.1.617.2 | 60 | 100% (3/3) |
| Italy-INMI1 | 60 | 100% (3/3) |
| Hong Kong/VM20001061/2020 | 60 | 100% (3/3) |
| USA-WA1/2020 | 60 | 100% (3/3) |
| Omicron lineage BA.1 | 60 | 100% (3/3)b |
| Omicron lineage BA.1.1 | 60 | 100% (3/3) |
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| Strain | Concentration(copies/wand) | Percent Detected (n/3) |
|---|---|---|
| Omicron lineage BA.2† | 60 | 100% (3/3) |
| Omicron lineage BA.5† | 60 | 100% (3/3) |
"Two cancelled tests were repeated.
b One invalid result was repeated.
& genomic RNA was used for this strain instead of inactivated virus.
Additionally, inclusivity was assessed by in silico analysis of the test primers/probe sequences against the genome sequences of 353.513 SARS-CoV-2 variants circulating in the United States between March 2022 and November 2022 and deposited in the NCBI and GISAID databases. For strains showing mismatches to the test primers/probe, risk level was then assigned as follows:
- · Risk level 1
- · A single mismatch was found in the forward and/or reverse primer alone.
- o A single mismatch was found at the 5' or 3' end of the probe.
- O Up to three deletions in the middle of the probe
- · Risk level 2
- · A single mismatch in the middle of the probe.
- One to two mismatches found anywhere in the probe in addition to one to two mismatches in the forward and/or reverse primer.
- · Up to three deletions in the middle of the probe combined with a single mismatch in the middle of the probe.
Of strains found to be circulating between March 2022 and November 2022, 98.853% had no mismatches, 0.738% of strains were determined to be in risk level 1 and 0.415% of strains were determined to be in risk level 2. Mismatches were further investigated by creating 21 synthetic templates representative of the mismatches found across strains in risk levels 1 and 2. Synthetic templates were spiked onto swabs at various concentrations and tested using the Cue COVID-19 Molecular Test. Fourteen of these were detected at 60 copies/wand and seven were detected at between 200 and 600 copies/wand.
Cue Health continues to perform monthly surveillance of emerging SARS-CoV-2 strains by evaluating the test primers/probe, in silico, against sequences deposited in the NCBI and GISAID databases. Updated information on detection of emerging variants of concern can be found at www.cuehealth.com.
-
- Assay Cut-Off:
The assay cutoff was determined in a limit of blank (LoB) study conducted in accordance with CLSI EP17-A2 as the 97th percentile of blank samples results.
- Assay Cut-Off:
9. Accuracy (Instrument):
Please refer to Section VI.C (Clinical Studies) for the clinical evaluation study and data that establish clinical performance and accuracy of the test device.
10. Carry-Over:
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A study was conducted to demonstrate that there is no carryover between samples when using the Cue Reader. In this study, negative clinical matrix samples were processed on the same reader following a high positive sample. In total sixteen samples of alternating negative and positive were run on five Cue Readers each for a total of 40 positive observations and 40 negative observations. All test results were as expected. No evidence of carryover was observed.
B Comparison Studies:
1. Method Comparison:
Please refer to Section VI.C (Clinical Studies) below for the clinical validation, regarding the method comparison studies.
-
- Matrix Comparison: Not Applicable.
C Clinical Studies:
A prospective all-comer study enrolled subjects at 13 sites, from December 2020 - February 2021 and November 2021- February 2022 to evaluate the clinical performance of the Cue COVID-19 Molecular Test in symptomatic individuals. Cue system set-up, sample collection, and testing were completed by each subject in a simulated home environment. Each subject was allowed " minutes to obtain a Cue COVID-19 Molecular Test result, including a retest if needed due to an initial canceled test or invalid result. A nasal swab sample was then collected by a trained operator for comparator testing. A consensus comparator (agreement between at least two FDA Emergency Use Authorized (EUA) molecular tests for SARS-CoV-2) was used for method comparison.
(DICS) One subject was excluded due to a protocol deviation; subjects were excluded due to no available Cue result; Subjects were excluded due to no available comparator result. There were 902 evaluable subjects with (b)(4) 1902) male (0)(4) 1902) female, 000 nonbinary, and with unreported gender. The age of participants ranged from 18 years old to 87 years old, with a mean of 40.9 years. The education level of subjects ranged from high school to post-graduate. Results obtained with the Cue COVID-19 Molecular Test were compared to the results obtained with the consensus comparator to determine clinical performance. The results are presented in Table 8.
| EUA authorized RT-PCRConsensus Comparator | Total | ||
|---|---|---|---|
| Pos | Neg | ||
| Cue Pos | 130 | 10 | 140 |
| Cue Neg | 10 | 752 | 762 |
| Total | 140 | 762 | 902 |
Table 8. Clinical performance of the Cue COVID-19 Molecular Test.
Positive Percent Agreement (PPA) = 92.9% (130/140) (95% CI: 87.4% = 96.1%) .
- Negative Percent Agreement (NPA) = 98.7% (752/762) (95% CI: 97.6% 99.3 %) .
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-
- Clinical Sensitivity:
Please refer to Section VI.C (Clinical Studies) above for the clinical validation. The PPA for the test is 92.9% (130/140) (95% CI: 87.4% - 96.1%)
- Clinical Sensitivity:
-
- Clinical Specificity:
Please refer to Section VI.C (Clinical Studies) above for the clinical validation. The NPA for the test is 98.7% (752/762) (95% CI: 97.6% - 99.3%)
- Clinical Specificity:
D Clinical Cut-Off:
There is no clinical cutoff related to the presence of SARS-CoV-2 in patient samples. This section is therefore not applicable.
E Expected Values/Reference Range:
In the Cue COVID-19 Molecular Test clinical study (described in the "Clinical Studies" section above), 246 anterior nasal swab specimens, collected during December 2020 - February 2021 and 656 anterior nasal swab specimens, collected during November 2021- February 2022, were determined to be evaluable. The number and percentage of SARS-CoV-2 positive cases per collection period, as determined by the Cue COVID-19 Molecular Test, are:
- (0)(4) . Positivity from December 2020 - February 2021 = (246)
- Positivity from December 2020 February 2021 = . V656) (0)(4)
F Other Supportive Performance Characteristics Data:
1. Usability and User Comprehension
A usability was conducted to assess lay users' execution of Cue Reader set up and Cue COVID-19 Molecular Test workflow. A total of 95 subjects, ages 18 years and older, were enrolled in the study. 98% (93/95) successfully completed testing by receiving a Negative or Positive result for the initial test or upon retest. One subject did not receive a valid Cue test result because no more test cartridges remained for a retest. One subject received a canceled test upon both initial testing and retesting.
Following the usability portion of the study, all subjects were issued a questionnaire. User comprehension was also assessed via a questionnaire completed by 776 subjects enrolled in the clinical study. The questionnaire assessed users' understanding of label comprehension concepts such as the test purpose, interpretation of results, and follow-up actions. The outcome of the study was used to validate the mitigations in the labeling.
2. Frequently Asked Questions
To improve user label comprehension, the labeling includes a Frequently Asked Questions (FAQ) section. The FAQ section was created to provide users information to adequately understand the purpose, limitations, and meaning of the test results as well as where users can access additional information regarding SAR-CoV-2 pathology and epidemiology. The concepts covered in the FAO section include:
- The purpose of the test and description of the test and the analyte. .
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- Who should and who should not use the test (self-selection). .
- Meaning of the test results. .
- . When to re-test (e.g., following an invalid result).
- Follow-up for appropriate health management. .
3. Hazard Analysis
A comprehensive hazard analysis of the Cue COVID-19 Molecular Test was conducted in accordance with ISO 14971:2019. The hazard analysis included identification of the potential hazard, likelihood of occurrence, severity of potential harm, hazard control measure(s), hazard control verification, and assignment of pre- and post-control risk levels. The elements considered included operator errors (i.e., human factors), sample and device handling and storage, and environmental factors.
Potential sources of errors that could adversely affect system performance were identified and mitigated first through system design and then through additional cautions in the labeling. The identified risks which could result in erroneous test results were evaluated in flex studies that evaluated the functionality of fail-safe mechanisms and stressed the functional limits of the test system (see below)
4. Failsafe Features
The device features a number of failsafe features designed to minimize false results due to user error:
- . Internal Control - Monitors for presence of human specimen material; monitors for the execution of each step in the test chemical reaction.
- Internal system timer Monitors for system timing with respect to cartridge and wand . insertion; monitors for correct wand insertion.
- . Tilt sensor - Monitors for correct test system positioning.
- Temperature Sensor Monitors test system temperature; prevents use of cartridges which . are not equilibrated to room temperature.
- . Cartridge Expiration date sensor - Prevents use of expired cartridges.
- Used Cartridge sensor Prevents use of used cartridges. .
- Battery Charge Sensor Prevents use of test system when the Cue Reader battery is < . 10% charged.
5. Flex Studies
The operational limits of the device were evaluated in a series of experiments simulating conditions of use outside of the intended use environment or in instances of user errors by testing positive (at 3x LoD) and negative samples were Cue sample wands with nothing spiked onto the swab.
The results demonstrated that the test system is robust and that false results can be expected to be reasonably mitigated through the combination fail-safes and labeling.
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| Study# | Sourceof Error | Objective | Description | Results |
|---|---|---|---|---|
| 1a | ImproperWandInsertion | Fail-safe verification -verify that a Sample Wandinserted 30 minutes afterthe test cartridge has beeninserted into the Readerand after the cartridge hascompleted heating willresult in a canceled test. | Once the cartridgefinished heating a timerwas started for 30minutes. After aminimum of 30 minutes,a blank Sample Wandwas inserted. | 29/29 tests were cancelled and theappropriate reason was displayed on the CueHealth App screen. |
| 1b | ImproperWandInsertion | Fail-safe verification -verify that a Sample Wandinserted prior to the testcartridge completingheating will result in acanceled test. | Immediately after thecartridge was inserted(before preheating wascompleted), a blanksample wand wasinserted into thecartridge. | 29/29 tests were cancelled and theappropriate reason was displayed on the CueHealth App screen. |
| Ic | ImproperWandInsertion | Fail-safe verification -verify a Sample Wand notfully inserted into the testcartridge shall not initiatea test and will result in acanceled test after 30minutes. | When prompted by theCue Health App, a blanksample wand was slowlyinserted but not all theway. | 29/29 tests were cancelled and theappropriate reason was displayed on the CueHealth App screen. |
| 1d | ImproperWandInsertion | Fail-safe verification -verify a Sample Wandinserted into the cartridgeprior to the cartridge beinginserted in the Reader,will result in a canceledtest. | A blank sample wandwas inserted into thecartridge, and then thecartridge (with SampleWand) was inserted intothe Reader. | 29/29 tests were cancelled and theappropriate reason was displayed on the CueHealth App screen. |
| 1e | Delay inTesting | Environmental Stress -assess test performanceusing samples that are notimmediately tested. | Negative and positivesamples were incubatedat room temperature forfive different timedurations prior to testing.Samples were then testedaccording to the userinstructions | < 1min hold time• 0/5 negative samples detected.• 5/5 positive samples detected.5 min hold time• 0/5 negative samples detected.• 5/5 positive samples detected.10 min hold time• 0/5 negative samples detected.• 4/5 positive samples detected.15 min hold time• 0/5 negative samples detected.• 5/5 positive samples detected.30 min hold time• 0/5 negative samples detected.• 5/5 positive samples detected.Overall, there was one false negative result.False results are mitigated by instructions tocollect and test samples immediately. |
| Study# | Sourceof Error | Objective | Description | Results |
| 2a | ImproperStorageConditions | Environmental Stress -assess open pouchstability of cartridges | Test cartridges wereunpackaged andincubated at 15℃ and30℃ for 30 and 40minutes each. Each timepoint and temperaturewas tested using bothnegative and positivesamples according to theuser instructions. | 15 ℃ and 30 min hold time0/5 negative samples detected.5/5 positive samples detected.15 ℃ and 40 min hold time1/10 negative samples detected.5/5 positive samples detected.30 ℃ and 30 min hold time0/5 negative samples detected.5/5 positive samples detected.30 ℃ and 40 min hold time0/5 negative samples detected.9/10 positive samples detectedOverall, there was one false negative resultand one false positive result. False results aremitigated by instructions to open thecartridge only when ready to test. |
| 2b | ImproperStorageConditions | Environmental Stress -assess open pouchstability of cartridgesexposed to sunlight for upto the duration of theclaimed in-use stability(30 minutes after openingthe pouch) | Test cartridges wereunpackaged andincubated on a surfacethat was exposed tosunlight for 10, 20, and30 minutes. Each timepoint was tested usingboth negative andpositive samplesaccording to the userinstructions. | 10 min hold time0/20 negative samples detected.Two initial canceled tests wereretested.20/20 positive samples detected.20 min hold time0/20 negative samples detected.Four initial canceled tests wereretested20/20 positive samples detected.One initial canceled test wasretested.30 min hold time0/20 negative samples detected.19/20 positive samples detected.Overall, there was one false negative result.False results are mitigated by instructions toopen the cartridge only when ready to test. |
| 2c | ImproperStorageConditions | Environmental Stress -assess the stability ofcartridges stored frozen,then brought back to roomtemperature | Test cartridges werestored in final packagingfor 72 hours at -20°C.Cartridges were allowedto acclimate to normaltemperature for 12 hours.Testing was thenperformed using bothnegative and positivesamples according to theuser instructions. | 0/20 negative samples were detected and19/20 positive samples were detected.Overall, there was one false negative result.False results are mitigated by proper storageconditions in the labeling. |
| 2d | ImproperStorageConditions | Environmental Stress -assess the stability ofcartridges storedrefrigerated, then broughtback to room temperature. | Test cartridges werestored in final packagingfor 72 hours at 2℃ to8°C and for 72 hours.Cartridges were allowedto acclimate to normaltemperature for 12 hours.Testing was performedusing both negative andpositive samplesaccording to the userinstructions. | 0/20 negative samples were detected and20/20 positive samples were detected. |
| Study# | Sourceof Error | Objective | Description | Results |
| 2e | ImproperStorageConditions | Fail-safe verification -verify that the systemrecognizes cartridgesstored refrigerated and notbrought back to roomtemperature. | Test cartridges werestored in final packagingfor 72 hours at 2°C to8°C and for 72 hours.Cartridges were theninserted into the Readerimmediately according tothe user instructions. | 20/20 tests were cancelled and theappropriate reason was displayed on the CueHealth App screen. |
| 2f | ImproperStorageConditions | Fail-safe verification -verify that the systemrecognizes the cartridgesare beyond the Use ByDate | Expired cartridges wereinserted into the Readeraccording to the userinstructions. | 20/20 tests were cancelled and theappropriate reason was displayed on the CueHealth App screen. |
| 2g | ImproperStorageConditions | Fail-safe verification -verify that the systemrecognizes the cartridgeshave been previously used | Used cartridges wereinserted into the Readeraccording to the userinstructions. | 20/20 tests were cancelled and theappropriate reason was displayed on the CueHealth App screen. |
| 3 | Functionality oftheInternalControl | Fail-safe Verification -Tovalidate the functionalityof the internal control | When prompted by theCue health App, a blanksample wand wasinserted into the cartridgeaccording to the userinstructions. | 38/40 tests returned an invalid result.Two tests returned a negative result. Failureof the internal control to detect humanspecimen is mitigated by detailed collectioninstructions. |
| 4a | ImproperPositioning | Fail-safe verification -To verify that a test willnot start if the Reader istilted to 20 degrees. | A tilt table was used toposition the Cue Readersuch that the cartridgeport was tilted at 20degrees in each of fourdirections (up, down, left,and right). A testcartridge was theninserted into the Reader. | For all 12 inserted cartridges (3 at each of tiltdirection), the test was not initiated, and theuser was provided with the appropriate tiltwarning message to return the Reader to aflat level surface to continue testing. |
| 4 b | ImproperPositioning | Fail-safe verification -verify that the test willcancel if the Reader istilted to between 20 and45 degrees during a testcycle and is not returnedto less than 20 degreeswithin 12 seconds. | When prompted by theCue Health App. a blanksample wand wasinserted into the cartridgeaccording to the userinstructions. A tilt tablewas then used to positionthe Cue Reader such thatthe cartridge port wastilted at between 20 and45 degrees in each offour directions (up,down, left, and right). | For all 12 samples (3 at each of tiltdirection), the test was canceled within 12seconds and the appropriate reason wasdisplayed on the Cue Health App screen. |
| 4c | ImproperPositioning | Fail-safe verification -verify the test will cancelif the Reader is tilted togreater than 45 degreesduring a test cycle. | When prompted by theCue Health App. a blanksample wand wasinserted into the cartridgeaccording to the userinstructions. A tilt tablewas then used to positionthe Cue Reader such thatthe cartridge port wastilted at greater than 45degrees in each of fourdirections (up, down, left,and right). | For all 12 samples (3 at each of tiltdirection), the test was canceled as soon asthe reader exceeded 45 degrees and theappropriate reason was displayed on the CueHealth App screen. |
| Study# | Sourceof Error | Objective | Description | Results |
| 4d | ImproperPositioning | Environmental Stress -assess test performancewith the reader tiltedbetween 18 and 20degrees. | A Cue reader was placedon an angled surface suchthat the cartridge portwas tilted at between 18and 20 degrees in each offour directions (up,down, left, and right).Each tilt direction wastested using bothnegative and positivesamples according to theuser instructions. | Up tilt• 0/5 negative samples detected.• 5/5 positive samples detected.Down tilt• 0/5 negative samples detected.• 5/5 positive samples detected.Left tilt• 0/5 negative samples detected.• 5/5 positive samples detected.Right tilt• 0/5 negative samples detected.• 5/5 positive samples detected. |
| 5a | Vibrations | Environmental Stress -assess test performancewith vibration of theReader and Cartridgealong the x profile. | A Cue Reader wassubject to vibrationalmotion in the horizontalX direction in accordancewith IEC 60068 2-64:2000 'Spectrum A2'Vibration (BroadbandRandom). Then bothnegative and positivesamples were runaccording to the userinstructions. Vibration ofthe entire systemcontinued throughouttesting. | 0/58 negative samples were detected. Therewas one invalid result and one cancelled test.59/60 positive samples were detected.Overall there was one false negative result.False results are mitigated by warnings not tomove the Cue Reader while the test isrunning. |
| 5b | Vibrations | Environmental Stress -assess test performancewith vibration of theReader and Cartridgealong the y profile. | A Cue Reader wassubject to vibrationalmotion in the horizontalY direction in accordancewith IEC 60068 2-64:2000 'Spectrum A2'Vibration (BroadbandRandom). Then bothnegative and positivesamples were runaccording to the userinstructions. Vibration ofthe entire systemcontinued throughouttesting. | 2/58 negative samples were detected. Therewas one invalid result. 59/59 positivesamples were detected. There was onecancelled test.Overall there were two false positive results.False results are mitigated by warnings not tomove the Cue Reader while the test isrunning. |
| 5c | Vibrations | Environmental Stress -assess test performancewith vibration of theReader and Cartridgealong the z profile. | testing.A Cue Reader wassubject to vibrationalmotion in the vertical Zdirection in accordancewith IEC 60068 2-64:2000 "Spectrum A2"Vibration (BroadbandRandom). Then bothnegative and positivesamples were runaccording to the userinstructions. Vibration ofthe entire systemcontinued throughouttesting. | running.1/59 negative samples were detected. Therewas one cancelled test. 60/60 positivesamples were detected.Overall there was one false positive result.False results are mitigated by warnings not tomove the Cue Reader while the test isrunning. |
| Study# | Sourceof Error | Objective | Description | Results |
| 6 | AtmosphericPressure | Environmental Stress -assess the performance ofthe Cue Cartridge Readerwith the Cue COVID-19Test Cartridge at "high"altitude. | Positive and negativesamples were runaccording to the userinstructions at highaltitude (2600m/8530ft). | 0/30 negative samples were detected and30/30 positive samples were detected. |
| 7 | Lightingconditions | Environmental Stress -verify that the ReaderLEDs are visible outdoors. | The Reader waspositioned on a tableunder normal daytimeconditions and the viewerwas 1 meter away fromthe Reader. 6 LED lightactivations on each of 3Readers were performed. | all 6 LED combinations were accuratelycalled by the 3 viewers from 1 meter away. |
| 8a | Electrica1 Power | Fail-safe Verification -verify that a test willcancel if the Reader is notdirectly connected to apower supply and runs outof battery charge duringtest processing | Readers with a deadbatteries were charged tobetween 1% and 3%. Acartridge was insertedand then prompted by theCue Health app, a blanksample wand wasinserted into the cartridgeaccording to the userinstructions. TheReader's battery wasdepleted before the testcompleted processing.The Reader was pluggedback in to record theresult. | 3/3 tests were cancelled and the appropriatereason was displayed on the Cue Health Appscreen. |
| 8b | Electrica1 Power | Environmental Stress -verify the testing processwill not be interrupted bypower fluctuations viaelectrical fast transientbursts. | Positive and negativesamples were testedaccording to the userinstructions. Readerswere subjected toelectrical fast transientbursts, in accordancewith IEC 61000-4-4, | 0/3 negative samples were detected. 3/3positive samples were detected. There wasone cancelled test that was re-run. |
| 8c | Electrica1 Power | Environmental Stress -verify the testing processwill not be interrupted bypower fluctuations viaelectrical surges. | during test processing.Positive and negativesamples were testedaccording to the userinstructions. Readerswere subjected to powerfluctuations via electricalsurges, in accordancewith IEC 61000-4-4.during test processing. | 0/3 negative samples were detected. 3/3positive samples were detected. |
| 8d | Electrica1 Power | Environmental Stress -verify that the testingprocess will not beinterrupted by powerfluctuations via electricalvoltage dips/interruptions. | Positive and negativesamples were testedaccording to the userinstructions. Readerswere subjected toelectrical voltagedips/interruptions, inaccordance with IEC61000-4-4, during testprocessing. | 0/3 negative samples were detected. 3/3positive samples were detected. |
| Study# | Sourceof Error | Objective | Description | Results |
| 8e | Electrica1 Power | Fail-safe Verification -verify a test will not startif the Reader is below10% battery level. | Using Readers withbattery level less than10%, a test cartridge wasinserted into the Reader. | For all three cartridges, the test did not start,and the Cue Health App provided a ReaderBattery Low warning, with instructions toconnect the Reader directly to a powersource to continue with the testing process. |
| 8f | Electrica1 Power | Environmental Stress -verify that testing can becompleted with the Readerat a 10% battery level. | Using Readers withbattery level at 10%, atest cartridge wasinserted into the Reader.Both positive andnegative samples wererun according to the userinstructions. | 0/3 negative samples were detected. 3/3positive samples were detected. |
| 9 | Dropping | Environmental Stress -assess test performanceafter dropping the testcartridge and Reader. | Ten cartridges and fiveReaders were bothdropped from a height ofthree feet. Both positiveand negative sampleswere run according to theuser instructions usingthe dropped items. | Dropped Cartridges• 0/5 negative samples detected.• 5/5 positive samples detected.Dropped Readers• 0/5 negative samples detected.• 5/5 positive samples detected. |
The following test cases evaluated the effectiveness of the fail-safes on device performance:
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VII Proposed Labeling:
The labeling supports the decision to grant the De Novo request for this device.
| Identified Risks to Health | Mitigation Measures |
|---|---|
| False Results | Certain labeling information includinglimitations, device descriptions, performanceinformation, and explanations of proceduresas identified in special controls (1), (2), (3),(4), (5).Certain design verification and validationincluding documentation of devicedescriptions, certain analytical studies andclinical studies, risk analysis strategiesidentified in special control (6).Testing of characterized viral samples andlabeling information identified in specialcontrol (7). |
| Failure to correctly interpret test results | Certain labeling information includinglimitations, device descriptions, performanceinformation, and explanations of proceduresas identified in special controls (1), (2), (3),(4), (5).Certain design verification and validationincluding documentation of devicedescriptions, certain analytical studies and |
Identified Risks and Mitigations: VIII
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| Identified Risks to Health | Mitigation Measures |
|---|---|
| clinical studies, risk analysis strategiesidentified in special control (6). | |
| Failure to correctly operate the device | Certain labeling information includinglimitations, device descriptions, performanceinformation, and explanations of proceduresas identified in special controls (1), (2), (3),(4), and (5).Certain design verification and validationincluding documentation of devicedescriptions, certain analytical studies andclinical studies, risk analysis strategiesidentified in special control (6). |
IX Benefit/Risk Assessment:
A Summary of the Assessment of Benefit:
The probable benefits of this device were found to include facilitating easy-to-use detection of COVID-19 in a home environment, with the potential to test an entire household using a single test reader with multiple cartridges. The unmet need met by this test is to allow for at-home performance of a rapid molecular IVD for SARS-CoV-2. Molecular tests are generally more sensitive and specific compared to the now widely available rapid antigen tests and have been considered the standard of care in guiding the isolation and treatment of patients with both symptomatic and asymptomatic COVID-19 in health care settings. Home-based testing for COVID-19 has several important advantages as detailed above, including decreasing time and effort requirements, shortening the time to diagnosis and therefore treatment, reducing infectious exposures during the process, and lessening demand on overburdened public health and clinical labs during times of increased transmission. For persons facing particular barriers to accessing care outside the home, whether due to physical factors (e.g., vision or mobility impairment), cognitive factors (e.g., learning disability or dementia), or demographic factors (e.g., low income, limited health literacy, geographic distance to medical facilities), at-home OTC tests may potentially help improve equity in early diagnosis, treatment, and improved outcomes of COVID-19.
B Summary of the Assessment of Risk:
The risks associated with the device, when used as intended, are those related to the risk of false or invalid test results, failure to correctly interpret the test results, and failure to correctly operate the device. False positive SARS-CoV-2 results may lead to unnecessary treatment for SARS-CoV-2 with antiviral medication, unnecessary isolation, and delayed diagnosis and treatment of other infections or health conditions. False negative SARS-CoV-2 results may lead to missing and not appropriately treating or monitoring a patient who has SARS-CoV-2 infection. False negative SARS-CoV-2 results may also lead to unnecessary additional diagnostic evaluation or treatment and delay in correct diagnosis or further spread of disease, which may lead to novel cases of infection and concomitant increase in patient morbidity and mortality. Invalid test results may lead to unnecessary delays while additional testing is sought, possibly leading to missed opportunity to initiate time-sensitive treatment, and/or to infecting additional persons.
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Compared to tests obtained in person with a HCP, OTC tests performed in the home environment carry the following additional risks: inadequate sample collection (resulting in an inadequate or contaminated sample), incorrect operation of the device (resulting in incorrect or invalid test results), and misinterpretation of test results by the lay user (resulting in incorrect diagnosis and/or actions, resulting in additional preventable harm to the health of the user or others).
C Summary of the Assessment of Benefit-Risk:
The device's performance observed in the clinical study suggests that errors will be uncommon and are mitigated by the device on-screen Labeling. The greatest magnitude of risk is that of inaccurate (mainly false negative, leading to a missed or delayed diagnosis of COVID-19, accompanied by the negative medical and epidemiologic consequences detailed above) test results combined with the absence of medical supervision, result interpretation, and care of a person with risk factors for severe disease. This risk is mitigated by providing repeated and clear guidance in the Labeling and IFU for the user to contact an HCP if evidence of worsening disease or risk factors for severe disease are present. With the addition of the special controls the benefits of this device to the intended use population and in the intended use settings presently outweigh the risks.
X Conclusion:
The De Novo request is granted, and the device is classified under the following and subject to the special controls identified in the letter granting the De Novo request:
Product Code(s): OWB Device Type: Over-the-counter molecular test to detect SARS-CoV-2 Class: II Regulation: 21 CFR 866.3984
N/A