(73 days)
Copan eNAT- molecular collection and preservation medium- is intended for the stabilization, transportation and inactivation of an unprocessed upper respiratory clinical specimen suspected of containing influenza A virus RNA. eNAT- molecular collection and preservation medium- is intended for use with compatible molecular assays.
The primary purpose of nucleic acids amplification techniques is to screen for a wide range of infectious diseases, so nucleic acid integrity of clinical specimens during transport and storage should be preserved.
eNAT® medium contains a detergent and a protein denaturant to prevent microbial proliferation and to maintains the integrity of the nucleic acids from cells or pathogens collected from patients and inactivates pathogen viability, thus eNAT® is not intended to be used for culture-based techniques.
Copan eNAT® has 3 different configurations:
Ref. 6U072S: a plastic screw-cap tube filled with 2 ml of Molecular Preservation and Transport medium.
Ref. 6U073S01: a plastic screw-cap tube filled with 2 ml of Molecular Preservation and Transport medium and a regular size tip nylon flocked swab for sample collection.
Ref. 6U074S01: a plastic screw-cap tube filled with 2 ml of Molecular Preservation and Transport and a minitip nylon flocked swab for sample collection.
The provided text details the 510(k) summary for the Copan eNAT® molecular collection and preservation medium. The document compares its performance to a predicate device, PrimeStore™ MTM, focusing on the inactivation and stabilization of Influenza A virus RNA.
Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided text:
Acceptance Criteria and Device Performance
1. Table of Acceptance Criteria and Reported Device Performance
| Performance Metric | Acceptance Criteria | Reported Device Performance (eNAT®) |
|---|---|---|
| Flu A Inactivation | >4.0 log reduction in concentration at 10 seconds (based on predicate device's criteria) | 4.5 log reduction (for Flu A in eNAT® at 10 seconds) |
| Flu A RNA Stability | +/- 3.0 Ct after 4 weeks storage at both 2-8°C and 25°C (compared to Time zero) | -0.2 ΔCt after 4 weeks at 2-8°C -0.1 ΔCt after 4 weeks at 25°C |
2. Sample Size Used for the Test Set and Data Provenance
The text explicitly mentions the following sample sizes and aspects of data provenance for the performance studies:
-
Flu A Inactivation Study:
- Test Set Description: High concentrations of Flu A in nasal matrix were inoculated into eNAT® using Copan's regular nasal-type FLOQSwabs®.
- Sample Size: Not explicitly stated as a number of distinct "samples." The study describes inoculating "aliquots" onto MDCK cell lines.
- Data Provenance: The study design "followed the study design described by Longhorn in the PrimeStore MTM Decision Summary, DEN170029." This suggests an in-house laboratory study. The country of origin for the data is not specified, but the applicant is Copan Italia S.p.A.
- Retrospective/Prospective: These appear to be prospective laboratory studies designed to evaluate the eNAT® device.
-
Analytical Sensitivity Study (LoD):
- Test Set Description: Flu A was diluted to 0.180 TCID50/ml (in the matrix) for testing with eNAT® in combination with the Cepheid Xpert® Xpress Flu/RSV assay.
- Sample Size: 24 replicates for the eNAT® samples.
- Data Provenance: Not explicitly stated but implied to be an in-house laboratory study.
- Retrospective/Prospective: Prospective laboratory study.
-
Flu A RNA Stability Study:
- Test Set Description: Flu A spiked into eNAT® medium.
- Sample Size: 24 replicates for each storage condition (Time zero, 4 weeks at 2-8°C, 4 weeks at 25°C).
- Data Provenance: Not explicitly stated but implied to be an in-house laboratory study.
- Retrospective/Prospective: Prospective laboratory study.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
The provided text does not mention the involvement of experts (such as radiologists) to establish ground truth for the test sets. The studies described are analytical performance studies conducted in a laboratory setting, rather than clinical studies requiring expert interpretation of diagnostic images or results. The "ground truth" for these studies is based on quantitative laboratory measurements of viral load or RNA levels.
4. Adjudication Method for the Test Set
As the studies are analytical performance assessments based on quantitative laboratory measurements (e.g., log reduction, TCID50/ml, PCR Ct values), adjudication methods (like 2+1 or 3+1 often used in clinical image interpretation studies) are not applicable and therefore not mentioned. The results are determined by the outcome of the laboratory assays.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size
No Multi-Reader Multi-Case (MRMC) comparative effectiveness study was done or is described. The studies detailed are analytical performance evaluations of the device's ability to inactivate and stabilize viral RNA, not clinical studies involving human readers and their diagnostic accuracy with or without AI assistance.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
The device itself is a molecular collection and preservation medium, not an algorithm. Therefore, the concept of "standalone performance" in the context of an algorithm does not apply here. The studies conducted evaluated the standalone performance of the medium in terms of its chemical and biological effects on the virus and its RNA.
7. The Type of Ground Truth Used
The ground truth used for these studies is analytical/laboratory-based:
- Flu A Inactivation: The ground truth for viral viability was determined by MDCK (Madin-Darby Canine Kidney) cell culture to measure cytopathic effect (CPE) and determine TCID50/ml (Tissue Culture Infectious Dose 50%).
- Analytical Sensitivity (LoD) and RNA Stability: The ground truth for the presence and quantity of Flu A RNA was established using a molecular assay (Cepheid Xpert® Xpress Flu/RSV assay), which provides quantitative PCR Ct values. The initial concentration of Flu A (TCID50/ml) was also a part of the ground truth for LoD.
8. The Sample Size for the Training Set
The provided text does not mention a training set as this device is a physical sample collection and preservation medium, not an AI/ML algorithm that requires training data. The studies are for performance validation of the medium itself.
9. How the Ground Truth for the Training Set Was Established
Since there is no training set mentioned for an AI/ML algorithm, this question is not applicable.
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Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, with the letters "FDA" in a blue square. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
Copan Italia S.p.A. Elena Simeonato Regulatory Affairs Manager Via F. Perotti 10 Brescia, Brescia 25125 Italy
September 17, 2020
Re: K201849
Trade/Device Name: eNAT molecular collection and preservation medium Regulation Number: 21 CFR 866.2950 Regulation Name: microbial nucleic acid storage and stabilization device Regulatory Class: Class II Product Code: QBD Dated: June 30, 2020 Received: July 6, 2020
Dear Elena Simeonato:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR
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- for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Kristian Roth, Ph.D. Chief Bacterial Respiratory and Medical Counter Measures Branch Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K201849
Device Name
eNAT - molecular collection and preservation medium-
Indications for Use (Describe)
Copan eNAT- molecular collection and preservation medium- is intended for the stabilization, transportation and inactivation of an unprocessed upper respiratory clinical specimen suspected of containing influenza A virus RNA. eNAT- molecular collection and preservation medium- is intended for use with compatible molecular assays.
Type of Use (Select one or both, as applicable)
| ☑ Prescription Use (Part 21 CFR 801 Subpart D) |
|---|
| ☐ Over-The-Counter Use (21 CFR 801 Subpart C) |
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5. 510 (K) SUMMARY
I. SUBMITTER
| Applicant Name: | Copan Italia S.p.A. |
|---|---|
| Via F. Perotti 10 | |
| 25125 Brescia, Italy | |
| Contact Person: | Elena Simeonato |
| Via F. Perotti, 10 | |
| Brescia, Italy | |
| Telephone: | +39 030 2687212 |
| Establishment Registration Number: | 3002444944 |
| Date Prepared: | June 30, 2020 |
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II. DEVICE - CLASSIFICATION
| Proprietary Name | eNAT® - molecular collection and preservation medium |
|---|---|
| Common/Usual Name | eNAT® |
| Device | Transport device for the stabilization of microbial nucleic acids |
| Classification Number | 21 CFR 866. 2950 |
| Product Code | QBD |
| Device Class | Class II |
| Review Panel | Microbiology |
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III. PREDICATE DEVICE – CLASSIFICATION
| Device Name | PrimeStore™ MTM |
|---|---|
| 510(k) Number | DEN170029 |
| Device | Transport device for the stabilization of microbialnucleic acids |
| Classification Number | 21 CFR 866. 2950 |
| Product Code | QBD |
| Device Class | Class II |
| Review Panel | Microbiology |
IV. INTENDED USE OF THE DEVICE
Copan eNAT - molecular collection and preservation medium - is intended for the stabilization, transportation and inactivation of an unprocessed upper respiratory clinical specimen suspected of containing influenza A virus RNA. eNAT- molecular collection and preservation medium- is intended for use with compatible molecular assays.
V. DEVICE DESCRIPTION
The primary purpose of nucleic acids amplification techniques is to screen for a wide range of infectious diseases, so nucleic acid integrity of clinical specimens during transport and storage should be preserved.
eNAT® medium contains a detergent and a protein denaturant to prevent microbial proliferation and to maintains the integrity of the nucleic acids from cells or pathogens collected from patients and inactivates pathogen viability, thus eNAT® is not intended to be used for culture-based techniques.
Copan eNAT® has 3 different configurations:
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Ref. 6U072S: a plastic screw-cap tube filled with 2 ml of Molecular Preservation and Transport medium.
Ref. 6U073S01: a plastic screw-cap tube filled with 2 ml of Molecular Preservation and Transport medium and a regular size tip nylon flocked swab for sample collection.
Ref. 6U074S01: a plastic screw-cap tube filled with 2 ml of Molecular Preservation and Transport and a minitip nylon flocked swab for sample collection.
VI. COMPARISON OF TECHNOLOGICAL CHARACTERISTICS WITH THE PREDICATE DEVICE
Copan eNAT® Molecular Collection and Preservation Medium is substantially equivalent in intended use and overall function to the commercially distributed device PrimeStore™ Molecular Transport Medium® by Longhorn Vaccines and Diagnostics LLC.
PrimeStore MTM™ by Longhorn Vaccines and Diagnostics LLC consists of a polypropylene tube containing 1 mL or 1.5 mL of a medium.
Copan eNAT® is provided ready to use in a polypropylene tube with a leak-proof screw-cap closure, containing 2mL of medium for the inactivation of influenza A (Flu A) and the stabilization of the Flu A RNA.
eNAT® and PrimeStore MTM™ medium show similar composition including the two active ingredients: guanidine thiocyanate and N-lauroylsarcosine (detergent). These components inactive Flu A. denature and lyse cells. and stabilize Flu A virus RNA.
eNAT® is also supplied in kit format consisting of the media-filled tube with either a regular nylon flocked swab or a minitip nylon flocked swab (Copan FLOQSwabs®), while PrimeStore MTM™ is supplied in tube format only. See Table 1: Side-by-Side Comparison of Copan eNAT® - molecular collection and preservation medium
Table 1: Side-by-Side Comparison of Copan eNAT® and Predicate Device.
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| Characteristics | Copan eNAT® Molecular Collectionand Preservation Medium | PrimeStore Molecular TransportMedium® DEN170029 (LonghornVaccines and Diagnostics LLC) |
|---|---|---|
| Collection deviceintended use | Copan eNAT® is intended for thecollection, inactivation and transport ofclinical specimens containing influenza Aviruses from the collection site to thetesting laboratory. eNAT® can beprocessed and used with compatiblemolecular assays the require stabilizationof nucleic acids from influenza A viruses | The PrimeStore MTM (#DEN170029) isintended for the stabilization, transportationand inactivation of infectious unprocessednasal washes suspected of containingInfluenza A virus RNA and is also intendedfor the stabilization, transportation andinactivation of infectious unprocessedsputum samples suspected of containingMycobacterium tuberculosis DNA fromhuman samples |
| Indication for use | eNAT® medium is a 'ready to use' systemthat allows for the stabilization and safetransport of clinical samples at ambienttemperature for viral RNA detection | PrimeStore MTM is a self-contained'ready to use' system that allows for thestabilization and safe transport of clinicalsamples at ambient temperature from thecollection site to the laboratory |
| Specimen Type | Respiratory specimens | Nasal washes and sputum samples |
| Microorganismnucleic acidspreserved | Influenza A virus | Influenza A virus and Mycobacteriumtuberculosis |
| Specimen stability | eNAT® medium preserves influenza ARNA for up to 28 days at 2-25°C. | Primestore MTM® medium preservesinfluenza A RNA for up to 8 days at 27°Cand 29 days at 4°C. |
| Inactivation testedon Flu A | >4.0 log reduction in concentration at 10seconds | Same |
| Container | Tube; plastic, conical bottom, | Same |
| self-standing with a screw cap | ||
| Medium | Tris-EDTA | TRIS |
| Formulation | Guanidine thiocyanateDetergentHEPESDistilled water | EDTAGuanidine thiocyanateN-lauroylsarcosine sodiumAntifoam ATCEPSodium citrateEthanolHClWater |
| Medium Volume | 2 mL | 1 mL or 1.5 mL |
| StorageTemperature | 2-25°C | Same |
| Shelf-life | 18 months | 24 months |
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VII. PERFORMANCE DATA
An inactivation study was conducted to verify that Copan eNAT® inactivates Flu A virus as efficiently as the predicate device PrimeStore MTM following the study design described by Longhorn in the PrimeStore MTM Decision Summary, DEN170029.
High concentrations of Flu A in nasal matrix were inoculated in eNAT® using Copan's regular nasaltype FLOQSwabs®. In particular, the swab was dipped into the infected matrix and used to transfer the sample into eNAT®.
The viability of the virus was measured after 10 seconds in eNAT® medium by inoculating aliquots onto MDCK (Madin-Darby Canine Kidney) cell lines, incubating for four days and measuring the cytopathic effect (CPE).
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The results for the inactivation study (Table 2) confirmed > 4.0 log reduction in Flu A titer in 10 seconds and demonstrates equivalent performance of eNAT® with PrimeStore MTM™ in the inactivation of influenza A.
| Sample | Viral load after 10s incubation | Log. reduction |
|---|---|---|
| CTRL+ (Flu A only) | 3.16*107 TCID50/ml | n/a |
| Flu A in eNAT® | ≤ 103 TCID50/ml | 4.5 |
Table 2: Summary of influenza A inactivation study results
An analytical sensitivity study was conducted to determine the Flu A limit of detection (LoD) obtained by eNAT® in combination with the Cepheid Xpert® Xpress Flu/RSV assay. eNAT® medium in combination with the Cepheid assay has reached the same LoD than UTM (reference device for the assay) and LoD has fallen within the range of TCID 50/ml declared by the Cepheid assay (0.75 -0.006 TCID50/ml in the matrix) for Flu A detection (Table 3) (Flu A 1 channel results shown).
Table 3: Summary of results obtained at the dilution corresponding to 0.180 TCIDs(/ml (in the matrix) during the Analytical Sensitivity Study using Xpert® Xpress Flu/RSV assay
| N° of positive replicates | eNAT® samples24/24 |
|---|---|
| Average PCR Ct obtained | 34.4 |
| Standard deviation | 0.93 |
| CV% | 2.7% |
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A stability study was designed to demonstrate that RNA from Flu A is preserved and stable in eNAT® medium. The stability of Flu A RNA in eNAT® was tested with the Cepheid Xpert® Xpress Flu/RSV Assay. The results of eNAT® influenza A RNA Stability Study (Table 4) (Flu A 1 channel results shown) confirmed that RNA stability in eNAT® met the acceptance criteria of +/- 3.0 Ct after 4 weeks storage at both 2-8°C and 25°C storage. The stability of RNA from Flu A spiked into nasal wash and stored in Longhorn PrimeStore MTM™ is 29 days at 4°C and 8 days at 27°C. This study demonstrates at least equivalent performance of eNAT® with PrimeStore MTM™ in the influenza A RNA stability.
| eNAT® samples | Results | |
|---|---|---|
| Time zero | N° of positive replicates | 24/24 |
| Average of PCR CTs | 30.8 | |
| St. Dev | 0.40 | |
| CV% | 1.3% | |
| PASS | yes | |
| 4 weeks @ 2-8°C | N° of positive replicates | 24/24 |
| Average of PCR CTs | 30.6 | |
| St. Dev | 0.20 | |
| CV% | 0.6% | |
| ΔCt 4w-T0 | -0.2 | |
| PASS | yes | |
| 4 weeks @ 25°C | N° of positive replicates | 24/24 |
| Average of PCR CTs | 30.7 | |
| St. Dev | 0.28 | |
| CV% | 0.9% | |
| ΔCt 4w-T0 | -0.1 | |
| PASS | yes |
Table 4: Flu A data in eNAT® at time zero and after 4 weeks at 2-8°C and 25°C
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VIII. CONCLUSIONS
Based on the above, Copan Italia S.p.A. believes that Copan eNAT® is substantially equivalent to the commercially distributed product PrimeStore MTM™ for the stabilization, inactivation and transportation of clinical specimens containing influenza A viruses from the collection site to the testing laboratory. No new issues of safety or effectiveness were found for Copan eNAT®.
§ 866.2950 Microbial nucleic acid storage and stabilization device.
(a)
Identification. A microbial nucleic acid storage and stabilization device is a device that consists of a container and reagents intended to stabilize microbial nucleic acids in human specimens for subsequent isolation and purification of nucleic acids for further molecular testing. The device is not intended for preserving morphology or viability of microorganisms.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The intended use for the labeling required under § 809.10 of this chapter must include a detailed description of microorganisms and types of human specimens intended to be preserved.
(2) The labeling required under § 809.10(b) of this chapter must include the following:
(i) A detailed device description, including all device components;
(ii) Performance characteristics from applicable analytical studies, including nucleic acid stability and microorganism inactivation;
(iii) A limiting statement that erroneous results may occur when the transport device is not compatible with molecular testing; and
(iv) A limiting statement that the device has only been validated to preserve the representative microorganisms used in the analytical studies.
(3) Design verification and validation must include the following:
(i) Overall device design, including all device components and all control elements incorporated into the analytical validation procedures;
(ii) Thorough description of the microorganisms and methodology used in the validation of the device including, extraction platforms and assays used for the detection of preserved nucleic acids; and
(iii) The limit of detection (LoD) of the molecular test used to establish microorganism nucleic acid stability.