(120 days)
The Aptima Combo 2® assay is a target amplification nucleic acid probe test that utilizes target capture for the in vitro qualitative detection and differentiation of ribosomal RNA (rRNA) from Chlamydia trachomatis (CT) and/or Neisseria gonorrhoeae (GC) to aid in the diagnosis of chlamydial and/or gonococcal disease using the Panther® system as specified.
On the Panther system, the assay may be used to test the following specimens from symptomatic and asymptomatic individuals: clinician-collected endocervical, PreservCyt® Solution liquid Pap specimens, vaginal, throat, rectal, and male urethral swab specimens; patient collected vaginal swab specimens , and female and male urine specimens.
¹Patient-collected vaginal swab specimens are an option for screening women when a pelvic exam is not otherwise indicated. The Aptima Multitest Swab Specimen Collection Kit has not been evaluated for home use.
The Aptima Combo 2® assay is a target amplification nucleic acid probe test that utilizes target capture for the in vitro qualitative detection and differentiation of ribosomal RNA (rRNA) from Chlamydia trachomatis (CT) and/or Neisseria gonorrhoeae (GC) to aid in the diagnosis of chlamydial and/or gonococcal urogenital disease using the Tigris® DTS® Automated Analyzer. The assay may be used to test the following specimens from symptomatic individuals: clinician-collected endocervical, vaginal and male urethral swab specimens; and female and male urine specimens. The assay may be used to test the following specimens from asymptomatic individuals: clinician-collected endocervical, vaginal and male urethral swab specimens; patient-collected vaginal swab specimens'; and female and male urine specimens. The assay is also intended for use with the testing of gynecological specimens, from both symptomatic and asymptomatic patients, collected in the PreservCyt® Solution.
1 Patient-collected vaginal swab specimens are an option for screening women when a pelvic exam is not otherwise indicated. The Aptima Multitest Swab Specimen Collection Kit is not for home use.
The Aptima Trichomonas vaginalis Assay is an in vitro qualitative nucleic acid amplification test (NAAT) for the detection of ribosomal RNA (rRNA) from Trichomonas vaginalis to aid in the diagnosis of trichomoniasis using the Panther System. The assay may be used to test the following specimens from symptomatic or asymptomatic women: clinician-collected endocervical swabs, clinician-collected vaginal swabs, and specimens collected in PreservCyt Solution.
The Aptima Trichomonas vaginalis Assay is an in vitro qualitative nucleic acid amplification test (NAAT) for the detection of ribosomal RNA (rRNA) from Trichomonas vaginalis to aid in the diagnosis of trichomoniasis using the Tigris® DTS® System. The assay may be used to test the following specimens from symptomatic or asymptomatic women: clinician-collected endocervical swabs, clinician-collected vaginal swabs, female urine specimens, and specimens collected in PreservCyt Solution.
The Aptima Combo 2 Assay (AC2) combines the technologies of target capture, TMA, and DKA. Specimens are collected and transferred into their respective specimen transport tubes. The transport solutions in these tubes release the rRNA targets and protect them from degradation during storage. When the Aptima Combo 2 Assay is performed in the laboratory, the target rRNA molecules are isolated from specimens by use of capture oligomers via target capture that utilizes magnetic microparticles. The capture oligomers contain sequences complementary to specific regions of the target molecules as well as a string of deoxyadenosine residues. A separate capture oligomer is used for each target. During the hybridization step, the sequence specific regions of the capture oligomers bind to specific regions of the target molecules. The capture oligomer:target complex is then captured out of solution by decreasing the temperature of the reaction to room temperature. This temperature reduction allows hybridization to occur between the deoxyadenosine region on the capture oligomer and the polydeoxythymidine molecules that are covalently attached to the magnetic particles. The microparticles, including the captured target molecules bound to them, are pulled to the side of the reaction vessel using magnets and the supernatant is aspirated. The particles are washed to remove residual specimen matrix that may contain amplification reaction inhibitors. After the target capture steps are completed, the specimens are ready for amplification.
Target amplification assays are based on the ability of complementary oligonucleotide primers to specifically anneal and allow enzymatic amplification of the target nucleic acid strands. The Aptima Combo 2 Assay replicates a specific region of the 23S rRNA from CT and a specific region of the 16S rRNA from GC via DNA intermediates. A unique set of primers is used for each target molecule. Detection of the rRNA amplification product sequences (amplicon) is achieved using nucleic acid hybridization. Single-stranded nucleic acid chemiluminescent probes, which are complementary to a region of each target amplicon, are labeled with different acridinium ester molecules. The updated version of the Aptima Combo 2 assay incorporates a second CT probe, complementary to a unique region of the existing CT amplicon. This tandem probe provides detection coverage for the variant strains of C. trachomatis that emerged in 2019. The labeled probes combine with amplicon to form stable hybrids. The Selection Reagent differentiates hybridized from unhybridized probe, eliminating the generation of signal from unhybridized probe. During the detection step, light emitted from the labeled hybrids is measured as photon signals in a luminometer and are reported as Relative Light Units (RLU). In DKA, differences in the kinetic profiles of the CT and GC labeled probes allow for the differentiation of signal; kinetic profiles are derived from measurements of photon output during the detection read time. The chemiluminescent detection for CT signal has very rapid kinetics and has the "flasher" kinetic type. The chemiluminescent detection for GC signal is relatively slower and has the "glower" kinetic type. Assay results are determined by a cut-off based on the total RLU and the kinetic curve type.
The Aptima Trichomonas vaginalis Assay (ATV) involves the technologies of target capture, transcription-mediated amplification (TMA), and hybridization protection assay (HPA). Specimens are collected and transferred into their respective specimen transport tubes. The transport solution in these tubes releases the rRNA target and protects it from degradation during storage. When the Aptima Trichomonas vaginalis Assay is performed in the laboratory, the target rRNA is isolated from the specimens by the use of a specific capture oligomer and magnetic microparticles in a method called target capture. The capture oligomer contains a sequence complementary to a specific region of the target molecule as well as a string of deoxyadenosine residues. During the hybridization step, the sequence-specific region of the capture oligomer binds to a specific region of the target molecule. The capture oligomer:target complex is then captured out of solution by decreasing the temperature of the reaction to room temperature. This temperature reduction allows hybridization to occur between the deoxyadenosine region on the capture oligomer and the poly-deoxythymidine molecules that are covalently attached to the magnetic particles. The microparticles, including the captured target molecule bound to them, are pulled to the side of the reaction vessel using magnets and the supernatant is aspirated. The particles are washed to remove residual specimen matrix that may contain amplification inhibitors. After the target capture steps are completed, the specimens are ready for amplification.
Target amplification assays are based on the ability of complementary oligonucleotide primers to specifically anneal and allow enzymatic amplification of the target nucleic acid strands. The Hologic TMA reaction amplifies a specific region of the small ribosomal subunit from T. vaginalis via DNA and RNA intermediates and generates RNA amplicon molecules. Detection of the rRNA amplification product sequences is achieved using nucleic acid hybridization (HPA). A single stranded chemiluminescent DNA probe, which is complementary to a region of the target amplicon, is labeled with an acridinium ester molecule. The labeled DNA probe combines with amplicon to form stable RNA:DNA hybrids. The Selection Reagent differentiates hybridized from unhybridized probe, eliminating the generation of signal from unhybridized probe. During the detection step, light emitted from the labeled RNA:DNA hybrids is measured as photon signals in a luminometer and are reported as Relative Light Units (RLU).
Acceptance Criteria and Device Performance for Aptima Combo 2 Assay and Aptima Trichomonas Vaginalis Assay (RMR Probe Reagent Update)
This document describes the acceptance criteria and the studies that demonstrate the device meets those criteria, specifically concerning the manufacturing change to the Ready-Made Reagents (RMR) Probe Reagent for the Aptima Combo 2 Assay (AC2) and Aptima Trichomonas Vaginalis Assay (ATV). The core of this submission is to prove that the removal of the lyophilization step for the RMR Probe Reagent does not negatively impact assay performance compared to the previously cleared predicate devices.
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are implicitly defined by demonstrating comparability to the predicate devices. The key performance metrics evaluated are Intended Use (overall agreement with expected positivity) and Limit of Detection (LoD). For clinical performance, the acceptance criteria are 100% agreement between the predicate and the modified RMR assay. For LoD, the acceptance criterion is that the RMR assay's LoD is within ½ log of the predicate assay's LoD.
| Performance Metric | Acceptance Criteria (Implicit: Comparability to Predicate) | Aptima Combo 2 Assay (Panther System) | Aptima Combo 2 Assay (Tigris System) | Aptima Trichomonas Vaginalis Assay (Panther System) | Aptima Trichomonas Vaginalis Assay (Tigris System) |
|---|---|---|---|---|---|
| Intended Use Study | 100% agreement with expected positivity for negative and positive panels. | CT: 100% Agreement (Expected) | CT: 100% Agreement (Expected) | TV: 100% Agreement (Expected) | TV: 100% Agreement (Expected) |
| GC: 100% Agreement (Expected) | GC: 100% Agreement (Expected) | ||||
| Limit of Detection (LoD) | LoD within ½ log of the predicate assay's LoD. | CT: LoD within ½ log (0.03 IFU/mL vs 0.1 IFU/mL) | CT: LoD within ½ log (0.003 IFU/mL vs 0.003 IFU/mL) | TV: LoD within ½ log (0.003 cells/mL vs 0.003 cells/mL) | TV: LoD within ½ log (0.01 cells/mL vs 0.01 cells/mL) |
| GC: LoD within ½ log (1 CFU/mL vs 0.3 CFU/mL) | GC: LoD within ½ log (0.3 CFU/mL vs 0.3 CFU/mL) | ||||
| FI-nvCT: LoD within ½ log (40 copies/mL vs 40 copies/mL) | FI-nvCT: LoD within ½ log (20 copies/mL vs 20 copies/mL) | ||||
| Clinical Performance Study (Agreement) | Positive Agreement (95% CI): Close to 100% Negative Agreement (95% CI): Close to 100% Overall Agreement (95% CI): Close to 100% | CT: PA: 100.0% (91.0%-100.0%) NA: 100.0% (97.9%-100.0%) OA: 100.0% (98.3%-100.0%) | CT: PA: 100.0% (89.8%-100.0%) NA: 100.0% (97.7%-100.0%) OA: 100.0% (98.1%-100.0%) | Not explicitly calculated for ATV, but stated to be comparable based on AC2 results. | Not explicitly calculated for ATV, but stated to be comparable based on AC2 results. |
| GC: PA: 100.0% (92.6%-100.0%) NA: 100.0% (97.8%-100.0%) OA: 100.0% (98.3%-100.0%) | GC: PA: 100.0% (92.4%-100.0%) NA: 100.0% (97.6%-100.0%) OA: 100.0% (98.1%-100.0%) |
2. Sample Size for the Test Set and Data Provenance
Intended Use Study:
- Aptima Combo 2 Assay (Panther): Negative and positive panels (exact number of panels or individual samples not specified, but stated to include CT positive, FI-nvCT positive, and CT/GC dual positive panels).
- Aptima Combo 2 Assay (Tigris): Negative and positive panels (exact number of panels or individual samples not specified, but stated to include CT positive, FI-nvCT positive, and CT/GC dual positive panels).
- Aptima Trichomonas Vaginalis Assay (Panther): Negative, TV positive, and TV low positive panels (exact number of panels or individual samples not specified).
- Aptima Trichomonas Vaginalis Assay (Tigris): Negative, TV positive, and TV low positive panels (exact number of panels or individual samples not specified).
- Data Provenance: Not explicitly stated, but these appear to be contrived panels (controlled positive and negative samples) rather than directly clinical specimens for this specific study.
Limit of Detection (LoD) Study:
- Aptima Combo 2 Assay (Panther & Tigris): Stocks of CT and GC organisms, and FI-nvCT in vitro transcript. These were run in negative clinical liquid pap specimens collected in PreservCyt solution (ThinPrep).
- Aptima Trichomonas Vaginalis Assay (Panther & Tigris): Stocks of TV organisms in negative clinical liquid pap specimens collected in PreservCyt solution (ThinPrep).
- Data Provenance: The base matrix used for spiking was "negative clinical liquid pap specimens," suggesting these are retrospective clinical samples from an unspecified origin, used in a prospective manner for LoD determination.
Clinical Performance Study:
- Aptima Combo 2 Assay (Panther): 219 remnant clinical swab specimens.
- Aptima Combo 2 Assay (Tigris): 200 remnant clinical swab specimens.
- Data Provenance: "remnant clinical swab specimens". This indicates these are retrospective samples collected from prior clinical testing, with the country of origin not specified.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
The ground truth for these studies is established by the performance of the predicate AC2 assay or ATV assay, which was previously cleared by the FDA. The document does not describe the involvement of additional human experts for the ground truth of these specific comparability studies, as the goal is to show the new RMR Probe Reagent performs equivalently to the already established predicate. The reliability of the predicate assays themselves would have been established through prior studies reviewed by the FDA, presumably involving expert consensus or validated methods.
4. Adjudication Method for the Test Set
Adjudication methods were not applicable in these studies. The assessment compares the performance of the modified AC2/ATV RMR assays directly against the predicate AC2/ATV assays. The predicate assay's result is used as the reference/ground truth for comparison. There is no mention of a separate expert adjudication process for discordant results between the predicate and the modified device in these comparability studies. In the LoD studies, the ground truth for spiked samples is defined by the known concentration of the spiked organisms/transcripts.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No MRMC comparative effectiveness study was done. This study concerns an in vitro diagnostic (IVD) device (nucleic acid amplification test) for direct detection of pathogens, not an AI-assisted diagnostic tool for human readers. Therefore, there is no human-in-the-loop performance to evaluate, and thus no effect size for human reader improvement with AI assistance.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance)
The studies presented are effectively standalone performance evaluations of the modified IVD assays. The assays are fully automated on the Panther and Tigris systems, and the results are interpreted based on predefined cut-offs (Relative Light Units and kinetic curve type). There is no human intervention in the result determination process once the assay is run. The comparison is between two versions of an automated assay.
7. Type of Ground Truth Used
- Intended Use Study: The "expected positivity results" indicate that calibrated positive and negative control panels (contrived ground truth) were used. These panels simulate clinical conditions but are created in a controlled laboratory setting.
- Limit of Detection (LoD) Study: The ground truth for LoD was spiked negative clinical specimens with known concentrations of target organisms/transcripts. This is a form of contrived ground truth based on quantitative standards.
- Clinical Performance Study: The ground truth for the clinical comparability study was the result of the predicate AC2 assay. This means the predicate assay's output was considered the reference standard, rather than an independent expert consensus or pathology review of the remnant specimens themselves for this specific comparability study. The performance of the predicate itself would have been validated against clinical outcomes or a gold standard during its initial clearance.
8. Sample Size for the Training Set
No training set is explicitly mentioned or relevant for this submission. This submission describes a manufacturing change to a reagent component of already cleared IVD assays. The assays are based on established molecular biology principles and do not involve machine learning algorithms that require a training set to "learn" patterns or make predictions. The "development activities" mentioned relate to design control and verification testing, not algorithmic training.
9. How the Ground Truth for the Training Set Was Established
As there is no training set for an algorithm, this question is not applicable.
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June 3, 2022
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Hologic, Inc. Jill Wyland Director, Regulatory Affairs 10210 Genetic Center Drive San Diego, California 92121
Re: K220321
Trade/Device Name: Aptima Combo 2 Assay (250 test kit) Panther. Aptima Combo 2 Assay (250 test kit) Tigris, Aptima Trichomonas Vaginalis Assay (250 test kit) Panther, Aptima Trichomonas Vaginalis Assay (250 test kit) Tigris Regulation Number: 21 CFR 866.3393 Regulation Name: Device To Detect Nucleic Acids From Non-Viral Microorganism(S) Causing Sexually Transmitted Infections And Associated Resistance Marker(S) Regulatory Class: Class II Product Code: QEP, LSL, OUY, MKZ Dated: February 2, 2022 Received: February 3, 2022
Dear Jill Wyland:
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.
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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 803) 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.
Himani Bisht. Ph.D. Assistant Director Viral Respiratory and HPV Branch Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Ouality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known)
Device Name
Indications for Use (Describe)
| 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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HOLOGIC®
510(k) SUMMARY
Aptima Combo 2 Assay (Panther and Tigris System) Aptima Trichomonas Vaginalis Assay (Panther and Tigris System)
I. SUBMITTER
Hologic, Inc. 10210 Genetic Center Drive San Diego, CA 92121
Contact Information:
| Jill Wyland | |
|---|---|
| Director of Regulatory & Quality | |
| Phone: | 858-410-8487 |
| Email: | jill.wyland@hologic.com |
Date Prepared: February 2, 2022
II. DEVICES
| Proprietary Name: | Aptima Combo 2® Assay (Panther System) |
|---|---|
| Classification Name: | Nucleic Acid Detection System for Non-Viral Microorganism(s) Causing Sexually Transmitted Infections |
| Regulation Number: | 866.3393 |
| Regulatory Class: | Class II |
| Product Code: | QEP |
| Subsequent Product Code: | MKZ, LSL |
| Proprietary Name: | Aptima Combo 2® Assay (Tigris System) |
| Classification Name: | Nucleic Acid Detection System for Non-Viral Microorganism(s) Causing Sexually Transmitted Infections |
| Regulation Number: | 866.3393 |
| Regulatory Class: | Class II |
| Product Code: | QEP |
| Subsequent Product Code: | MKZ, LSL |
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| Proprietary Name: | Aptima Trichomonas Vaginalis® Assay (Panther System) |
|---|---|
| Classification Name: | Trichomonas Vaginalis Nucleic Acid Amplification Test System |
| Regulation Number: | 866.3860 |
| Regulatory Class: | Class II |
| Product Code: | OUY |
| Proprietary Name: | Aptima Trichomonas Vaginalis® Assay (Tigris System) |
| Classification Name: | Trichomonas Vaginalis Nucleic Acid Amplification Test System |
| Regulation Number: | 866.3860 |
| Regulatory Class: | Class II |
| Product Code: | OUY |
III. PREDICATE DEVICES
The predicate devices are the following:
- o Aptima Combo 2 Assay (Panther System): K200866; cleared 05/17/2020)
- 0 Aptima Combo 2 Assay (Tigris System): K200866; cleared 05/17/2020)
- Aptima Trichomonas Vaginalis Assay (Panther System): K122062; cleared 01/09/2013) .
- Aptima Trichomonas Vaginalis Assay (Tigris System): K102911; cleared 04/19/2011)
These predicate devices have not been subject to a design-related recall.
IV. DEVICE DESCRIPTIONS
Aptima Combo 2 Assay
The Aptima Combo 2 Assay (AC2) combines the technologies of target capture, TMA, and DKA. Specimens are collected and transferred into their respective specimen transport tubes. The transport solutions in these tubes release the rRNA targets and protect them from degradation during storage. When the Aptima Combo 2 Assay is performed in the laboratory, the target rRNA molecules are isolated from specimens by use of capture oligomers via target capture that utilizes magnetic microparticles. The capture oligomers contain sequences complementary to specific regions of the target molecules as well as a string of deoxyadenosine residues. A separate capture oligomer is used for each target. During the hybridization step, the sequence specific regions of the capture oligomers bind to specific regions of the target molecules. The capture oligomer:target complex is then captured out of solution by decreasing
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the temperature of the reaction to room temperature. This temperature reduction allows hybridization to occur between the deoxyadenosine region on the capture oligomer and the polydeoxythymidine molecules that are covalently attached to the magnetic particles. The microparticles, including the captured target molecules bound to them, are pulled to the side of the reaction vessel using magnets and the supernatant is aspirated. The particles are washed to remove residual specimen matrix that may contain amplification reaction inhibitors. After the target capture steps are completed, the specimens are ready for amplification.
Target amplification assays are based on the ability of complementary oligonucleotide primers to specifically anneal and allow enzymatic amplification of the target nucleic acid strands. The Aptima Combo 2 Assay replicates a specific region of the 23S rRNA from CT and a specific region of the 16S rRNA from GC via DNA intermediates. A unique set of primers is used for each target molecule. Detection of the rRNA amplification product sequences (amplicon) is achieved using nucleic acid hybridization. Single-stranded nucleic acid chemiluminescent probes, which are complementary to a region of each target amplicon, are labeled with different acridinium ester molecules. The updated version of the Aptima Combo 2 assay incorporates a second CT probe, complementary to a unique region of the existing CT amplicon. This tandem probe provides detection coverage for the variant strains of C. trachomatis that emerged in 2019. The labeled probes combine with amplicon to form stable hybrids. The Selection Reagent differentiates hybridized from unhybridized probe, eliminating the generation of signal from unhybridized probe. During the detection step, light emitted from the labeled hybrids is measured as photon signals in a luminometer and are reported as Relative Light Units (RLU). In DKA, differences in the kinetic profiles of the CT and GC labeled probes allow for the differentiation of signal; kinetic profiles are derived from measurements of photon output during the detection read time. The chemiluminescent detection for CT signal has very rapid kinetics and has the "flasher" kinetic type. The chemiluminescent detection for GC signal is relatively slower and has the "glower" kinetic type. Assay results are determined by a cut-off based on the total RLU and the kinetic curve type.
Aptima Trichomonas Vaginalis Assay
The Aptima Trichomonas vaginalis Assay (ATV) involves the technologies of target capture,
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transcription-mediated amplification (TMA), and hybridization protection assay (HPA). Specimens are collected and transferred into their respective specimen transport tubes. The transport solution in these tubes releases the rRNA target and protects it from degradation during storage. When the Aptima Trichomonas vaginalis Assay is performed in the laboratory, the target rRNA is isolated from the specimens by the use of a specific capture oligomer and magnetic microparticles in a method called target capture. The capture oligomer contains a sequence complementary to a specific region of the target molecule as well as a string of deoxyadenosine residues. During the hybridization step, the sequence-specific region of the capture oligomer binds to a specific region of the target molecule. The capture oligomer:target complex is then captured out of solution by decreasing the temperature of the reaction to room temperature. This temperature reduction allows hybridization to occur between the deoxyadenosine region on the capture oligomer and the poly-deoxythymidine molecules that are covalently attached to the magnetic particles. The microparticles, including the captured target molecule bound to them, are pulled to the side of the reaction vessel using magnets and the supernatant is aspirated. The particles are washed to remove residual specimen matrix that may contain amplification inhibitors. After the target capture steps are completed, the specimens are ready for amplification.
Target amplification assays are based on the ability of complementary oligonucleotide primers to specifically anneal and allow enzymatic amplification of the target nucleic acid strands. The Hologic TMA reaction amplifies a specific region of the small ribosomal subunit from T. vaginalis via DNA and RNA intermediates and generates RNA amplicon molecules. Detection of the rRNA amplification product sequences is achieved using nucleic acid hybridization (HPA). A single stranded chemiluminescent DNA probe, which is complementary to a region of the target amplicon, is labeled with an acridinium ester molecule. The labeled DNA probe combines with amplicon to form stable RNA:DNA hybrids. The Selection Reagent differentiates hybridized from unhybridized probe, eliminating the generation of signal from unhybridized probe. During the detection step, light emitted from the labeled RNA:DNA hybrids is measured as photon signals in a luminometer and are reported as Relative Light Units (RLU).
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V. DESCRIPTION OF DEVICE MODIFICATION
As a convenience for customers processing high volume of assays, Hologic previously received clearance (K200436; cleared 03/23/2020) for a Ready-Made Reagents (RMR) format which allows customers to procure a liquid form (reconstituted) of the Amplification, Enzyme, and Probe Reagents for use on both the Tigris and Panther systems. At the time of clearance, the RMR Amplification and Enzyme reagents followed a validated manufacturing process which removed the lyophilization steps; however, the RMR Probe Reagent was still manufactured as a lyophilized reagent (cake form), and then just prior to shipping to customers, Hologic manufacturing personnel manually reconstituted the lyophilized Probe Reagent with the Probe Reconstitution Solution to reach a liquid form. Providing all three reagents in a RMR format (liquid form) allows the operator to follow the same processing steps for each reagent. The clearance of this Special 510(k) application allows for a manufacturing change to the RMR Probe Reagent to remove the lyophilization process to match the liquid manufacturing format of the RMR Amplification and Enzyme reagents. The manufacturing change does not change product design, principles of procedure, intended use, primary technological characteristics, or impact assay performance. The RMR Probe Reagent is the same formulation for either Aptima Combo 2 Assay or Aptima Trichomonas Vaginalis Assay, with the exception of the detection oligos, and is independent of the instrument platform.
VI. INDICATIONS FOR USE
There are no changes to the indications for use / intended use for each assay due to the manufacturing change of the RMR Probe Reagent.
Intended Use - Aptima Combo 2 (Panther)
The Aptima Combo 2® assay is a target amplification nucleic acid probe test that utilizes target capture for the in vitro qualitative detection and differentiation of ribosomal RNA (rRNA) from Chlamydia trachomatis (CT) and/or Neisseria gonorrhoeae (GC) to aid in the diagnosis of chlamydial and/or gonococcal disease using the Panther® system as specified.
On the Panther system, the assay may be used to test the following specimens from
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symptomatic and asymptomatic individuals: clinician-collected endocervical, PreservCyt® Solution liquid Pap specimens, vaginal, throat, rectal, and male urethral swab specimens; patient collected vaginal swab specimens , and female and male urine specimens.
¹Patient-collected vaginal swab specimens are an option for screening women when a pelvic exam is not otherwise indicated. The Aptima Multitest Swab Specimen Collection Kit has not been evaluated for home use.
Intended Use - Aptima Combo 2 (Tigris)
The Aptima Combo 2® assay is a target amplification nucleic acid probe test that utilizes target capture for the in vitro qualitative detection and differentiation of ribosomal RNA (rRNA) from Chlamydia trachomatis (CT) and/or Neisseria gonorrhoeae (GC) to aid in the diagnosis of chlamydial and/or gonococcal urogenital disease using the Tigris® DTS® Automated Analyzer. The assay may be used to test the following specimens from symptomatic individuals: clinician-collected endocervical, vaginal and male urethral swab specimens; and female and male urine specimens. The assay may be used to test the following specimens from asymptomatic individuals: clinician-collected endocervical, vaginal and male urethral swab specimens; patient-collected vaginal swab specimens'; and female and male urine specimens. The assay is also intended for use with the testing of gynecological specimens, from both symptomatic and asymptomatic patients, collected in the PreservCyt® Solution.
1 Patient-collected vaginal swab specimens are an option for screening women when a pelvic exam is not otherwise indicated. The Aptima Multitest Swab Specimen Collection Kit is not for home use.
Intended Use - Aptima Trichomonas Vaginalis (Panther)
The Aptima Trichomonas vaginalis Assay is an in vitro qualitative nucleic acid amplification test (NAAT) for the detection of ribosomal RNA (rRNA) from Trichomonas vaginalis to aid in the diagnosis of trichomoniasis using the Panther System. The assay may be used to test the following specimens from symptomatic or asymptomatic women: clinician-collected endocervical swabs, clinician-collected vaginal swabs, and specimens collected in PreservCyt Solution.
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Intended Use - Aptima Trichomonas Vaginalis (Tigris)
The Aptima Trichomonas vaginalis Assay is an in vitro qualitative nucleic acid amplification test (NAAT) for the detection of ribosomal RNA (rRNA) from Trichomonas vaginalis to aid in the diagnosis of trichomoniasis using the Tigris® DTS® System. The assay may be used to test the following specimens from symptomatic or asymptomatic women: clinician-collected endocervical swabs, clinician-collected vaginal swabs, female urine specimens, and specimens collected in PreservCyt Solution.
VII. COMPARISON OF TECHNILOGICAL CHARACTERISTICS WITH THE PREDICATE DEVICES
A comparison of the four subject devices (with new RMR Probe Reagent) to the predicate devices (with lyophilized Amplification, Enzyme, and Probe Reagents) are summarized in Table 1 through Table 4. Use of the RMR Probe Reagent does not change the principles of procedure, intended use, or primary technological characteristics. The similarities and differences between the subject and predicate devices are further discussed following the last substantial equivalence table. This discussion is the same for each assay.
| Item | AC2 Assay (Panther)(Predicate Device)K200866 | AC2Assay(Panther)(Subject Device) |
|---|---|---|
| TechnologyPrinciple ofOperation | Target Capture (TC), Transcription-Mediated Amplification(TMA), Hybridization Protection Assay (HPA) | Same |
| Platform | Automated Panther System | Same |
| Function | Detection and differentiation of rRNA from Chlamydiatrachomatis and Neisseria gonorrhoeae | Same |
| OrganismsDetected | Chlamydia trachomatis (CT) and/or Neisseria gonorrhoeae (GC) | Same |
| PatientPopulation | Symptomatic and asymptomatic individuals | Same |
| Intended Use | The Aptima Combo 2® assay is a target amplification nucleicacid probe test that utilizes target capture for the in vitroqualitative detection and differentiation of ribosomal RNA(rRNA) from Chlamydia trachomatis (CT) and/or Neisseriagonorrhoeae (GC) to aid in the diagnosis of chlamydial and/orgonococcal disease using the Panther® system as specified. Onthe Panther system, the assay may be used to test the following | Same |
Table 1: Comparison Between Predicate Device and Subject Device - AC2 on Panther
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| Item | AC2 Assay (Panther)(Predicate Device)K200866 | AC2Assay(Panther)(Subject Device) |
|---|---|---|
| specimens from symptomatic and asymptomatic individuals:clinician-collected endocervical, PreservCyt® Solution liquidPap specimens, vaginal, throat, rectal, and male urethral swabspecimens; patient collected vaginal swab specimens¹, andfemale and male urine specimens.¹Patient-collected vaginal swab specimens are an option for screeningwomen when a pelvic exam is not otherwise indicated. The AptimaMultitest Swab Specimen Collection Kit has not been evaluated forhome use. |
Table 2: Comparison Between Predicate Device and Subject Device - AC2 on Tigris
| Item | AC2 Assay (Tigris)(Predicate Device)K200866 | AC2 Assay (Tigris)(Subject Device) |
|---|---|---|
| TechnologyPrinciple ofOperation | Target Capture (TC), Transcription-Mediated Amplification(TMA), Hybridization Protection Assay (HPA) | Same |
| Platform | Automated Tigris System | Same |
| Function | Detection and differentiation of rRNA from Chlamydiatrachomatis and Neisseria gonorrhoeae | Same |
| OrganismsDetected | Chlamydia trachomatis (CT) and/or Neisseria gonorrhoeae (GC) | Same |
| PatientPopulation | Symptomatic and asymptomatic individuals | Same |
| Intended Use | The Aptima Combo 2® assay is a target amplification nucleicacid probe test that utilizes target capture for the in vitroqualitative detection and differentiation of ribosomal RNA(rRNA) from Chlamydia trachomatis (CT) and/or Neisseriagonorrhoeae (GC) to aid in the diagnosis of chlamydial and/orgonococcal urogenital disease using the Tigris® DTS®Automated Analyzer. The assay may be used to test thefollowing specimens from symptomatic individuals: clinician-collected endocervical, vaginal and male urethral swabspecimens; and female and male urine specimens. The assay maybe used to test the following specimens from asymptomaticindividuals: clinician-collected endocervical, vaginaland male urethral swab specimens; patient-collected vaginalswab specimens ; and female and male urine specimens. Theassay is also intended for use with the testing of gynecologicalspecimens, from both symptomatic and asymptomatic patients,collected in the PreservCyt® Solution.1 Patient-collected vaginal swab specimens are an option for screeningwomen when a pelvic exam is not otherwise indicated. The AptimaMultitest Swab Specimen Collection Kit is not for home use. | Same |
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| Item | ATV Assay (Panther)(Predicate Device)K122062 | ATV Assay (Panther)(Subject Device) |
|---|---|---|
| TechnologyPrinciple ofOperation | Target Capture (TC), Transcription-Mediated Amplification(TMA), Hybridization Protection Assay (HPA) | Same |
| Platform | Automated Panther System | Same |
| Function | Detection and differentiation of rRNA from Trichomonas vaginalis | Same |
| OrganismsDetected | Trichomonas vaginalis | Same |
| PatientPopulation | Symptomatic and asymptomatic individuals | Same |
| Intended Use | The Aptima Trichomonas vaginalis Assay is an in vitroqualitative nucleic acid amplification test (NAAT) for thedetection of ribosomal RNA (rRNA) from Trichomonasvaginalis to aid in the diagnosis of trichomoniasis using thePanther System. The assay may be used to test the followingspecimens from symptomatic or asymptomatic women:clinician-collected endocervical swabs, clinician-collectedvaginal swabs, and specimens collected in PreservCyt Solution. | Same |
Table 3: Comparison Between Predicate Device and Subject Device - ATV on Panther
Table 4: Comparison Between Predicate Device and Subject Device – ATV on Tigris
| Item | ATV Assay (Tigris)(Predicate Device)K102911 | ATV Assay (Tigris)(Subject Device) |
|---|---|---|
| TechnologyPrinciple ofOperation | Target Capture (TC), Transcription-Mediated Amplification(TMA), Hybridization Protection Assay (HPA) | Same |
| Platform | Automated Tigris System | Same |
| Function | Detection and differentiation of rRNA from Trichomonasvaginalis | Same |
| OrganismsDetected | Trichomonas vaginalis | Same |
| PatientPopulation | Symptomatic and asymptomatic individuals | Same |
| Intended Use | The Aptima Trichomonas vaginalis Assay is an in vitroqualitative nucleic acid amplification test (NAAT) for thedetection of ribosomal RNA (rRNA) from Trichomonasvaginalis to aid in the diagnosis of trichomoniasis using theTigris® DTS® System. The assay may be used to test thefollowing specimens from symptomatic or asymptomatic | Same |
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| Item | ATV Assay (Tigris)(Predicate Device)K102911 | ATV Assay (Tigris)(Subject Device) |
|---|---|---|
| women: clinician-collected endocervical swabs, clinician-collected vaginal swabs, female urine specimens, and specimenscollected in PreservCyt Solution. |
Similarities
Each of the subject devices utilize the same technology and principles of operation, mechanisms of action, conditions of use, results interpretation, have identical intended uses, and run on the same automated instrument system as compared to their predicate device. There are no differences in the performance of the assay or customer interface as a result of the RMR Probe manufacturing change.
Differences
During bulk manufacturing of the new RMR Probe Reagent, the lyophilization step is removed to match the liguid manufacturing format of the RMR Amplification and Enzyme reagents. Due to this manufacturing change, the part number for the RMR Probe reagent was updated along with a new catalog number to differentiate the RMR Probe product configuration from the current RMR format (using RMR Probe reconstituted in-house). The updated catalog number appears on the box label and in the assay package insert. There are no other labeling changes.
VIII. Design Control Activities
Hologic's overall product development activities are conducted per procedure, 'Product Development Procedure' which is in conformance with the design control requirements as specified in 21 CFR 820.30. Verification testing was performed to confirm clinical comparability between the predicate AC2 and ATV assays to the AC2 RMR and ATV RMR assays containing the new Probe Reagent. The completed verification studies demonstrate that the new RMR Probe Reagent does not impact assay performance, assay safety and effectiveness, and confirms that the modified assay meets the design input requirements.
Hologic risk analysis activities are conducted per Product Safety Risk Management Procedure which is in conformance with ISO 14971:2007. Based on the results of the risk analysis and
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verification activities, and in accordance with ISO 14971:2007, all risks are reduced as far as possible and meet the pre-defined acceptability criteria. There were no hazards that fell within the "Undesirable" or "Unacceptable" residual risk regions. The device modifications do not introduce any new hazards or increase the overall residual risk as compared to the currently marketed products.
IX. ASSAY PERFORMANCE
The following performance data are provided in support of the clearance of the AC2 and ATV RMR assays containing the new RMR Probe Reagent on the Panther system and Tigris system.
Intended Use Study
Aptima Combo 2 Assay (Panther)
A comparison of Intended Use results between the predicate AC2 assay and AC2 RMR assay (containing the new RMR Probe Reagent: termed 'RMR assay' throughout this document) on the Panther system showed comparability when negative and positive panels were tested. AC2 panels consisting of a Negative panel, CT positive, FI-nvCT positive, and CT/GC dual positive panels were run on two Panther instruments. The predicate AC2 assay was used as the baseline result. The results showed 100% agreement to the expected positivity results for each CT panel, FI-nvCT panel, GC panel, and with dual positive panel for both the predicate AC2 and AC2 RMR assays on Panther.
Aptima Combo 2 Assay (Tigris)
A comparison of Intended Use results between the predicate AC2 assay and AC2 RMR assay on the Tigris system showed comparability when negative and positive panels were tested. AC2 panels consisting of a Negative panel, CT positive, FI-nvCT positive, and CT/GC dual positive panels were run on one Tigris instrument. The predicate AC2 assay was used as the baseline result. The results showed 100% agreement to the expected positivity results for each CT panel, FI-nvCT panel, GC Panel and with dual positive panel for both the predicate AC2 assay and AC2 RMR assay on the Tigris system.
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Aptima Trichomonas vaginalis Assay (Panther)
A comparison of Intended Use results between the predicate ATV assay and ATV RMR assay on the Panther system showed comparability when negative and positive panels were tested. ATV panels consisting of a Negative panel, TV positive, and TV low positive were run on two Panther instruments. The current ATV assay was used as the baseline results showed 100% agreement to the expected positivity results for each TV panel, for both the predicate ATV and ATV RMR assays on the Panther system.
Aptima Trichomonas vaginalis Assay (Tigris)
A comparison of Intended Use results between the predicate ATV assay and ATV RMR assay on the Tigris system showed comparability when negative and positive panels were tested. ATV panels consisting of a Negative panel, TV positive, and TV low positive were run on one Tigris instrument. The predicate ATV assay was used as the baseline result. The results showed 100% agreement to the expected positivity results for each TV panel, for both the predicate ATV and ATV RMR assays on the Tigris system.
Limit of Detection
Aptima Combo 2 Assay (Panther)
The Limit of Detection (LoD) for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (GC), and Finnish new variant CT (FI-nvCT) for AC2 RMR assay was determined to be within ½ log of the LoD for the predicate AC2 assay on the Panther system. The limit of detection was estimated for the predicate AC2 and AC2 RMR assays by using stocks of CT and GC organisms as well as FI-nvCT in vitro transcript in negative clinical liquid pap specimens collected in PreservCyt solution (ThinPrep). These panels were tested on two Panther systems using two lots for each reagent format. The equivalency was shown as the results of the lowest concentration ≥ 95% positivity for CT target on the predicate AC2 assay (0.1 IFU/mL) and for AC2 RMR assay (0.03 IFU/mL) on the Panther were within ½ log. The equivalency for the GC target was equivalent as shown by the lowest concentration ≥ 95% positivity for the predicate AC2 assay (0.3 CFU/mL) and for the AC2 RMR assay (1 CFU/mL) on the Panther were within ½ log. The equivalency for the FI-nvCT target was equivalent as shown by the lowest concentration > 95%
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positivity for the predicate AC2 assay and for the AC2 RMR assay of 40 copies/mL on the Panther.
Aptima Combo 2 Assay (Tigris)
The Limit of Detection (LoD) for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (GC), and Finnish new variant CT (FI-nvCT) for AC2 RMR assay was determined to be within ½ log of the LoD for the predicate AC2 assay on the Tigris system. The limit of detection was estimated for the predicate AC2 and AC2 RMR assays by using stocks of CT and GC organisms as well as FI-nvCT in vitro transcript in negative clinical liquid pap specimens collected in PreservCyt solution (ThinPrep). These panels were tested on two Tigris systems using two reagent lots for each format. The equivalency was shown as the results of the lowest concentration ≥ 95% positivity for CT target on the predicateAC2 assay and for AC2 RMR assay on Tigris was 0.003 IFU/mL. The equivalency for the GC target was equivalent as shown by the lowest concentration > 95% positivity for the predicate AC2 assay and for the AC2 RMR assay on Tigris was 0.3 CFU/mL. The equivalency for the FI-nvCT target was equivalent as shown by the lowest concentration ≥ 95% positivity for the predicate AC2 assay and for the AC2 RMR assay on Tigris was 20 copies/mL.
Aptima Trichomonas vaginalis Assay (Panther)
The Limit of Detection (LoD) for Trichomonas vaginalis for ATV RMR assay was determined to be within ½ log of the LoD for the predicate ATV assay on the Panther System. The limit of detection was estimated for the predicate ATV and ATV RMR assays by using stocks of TV organisms in negative clinical liquid pap specimens collected in PreservCyt solution (ThinPrep). These panels were tested on two Panther systems using two lots for each reagent format. The equivalency was shown as the results of the lowest concentration > 95% positivity for TV target on the predicate ATV assay and for the ATV RMR assay on Panther was 0.003 cells/mL.
Aptima Trichomonas vaginalis Assay (Tigris)
The Limit of Detection (LoD) for Trichomonas vaginalis for ATV RMR assay was determined to be within ½ log of the LoD for the predicate ATV assay on the Tigris System. The limit of detection was estimated for the predicate ATV and ATV RMR assays by using stocks of TV
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organisms in negative clinical liquid pap specimens collected in PreservCyt solution (ThinPrep). These panels were tested on one Tigris system using two reagent lots for each format. The equivalency was shown as the results of the lowest concentration ≥ 95% positivity for TV target on the predicate ATV assay and for the ATV RMR assay on Tigris was 0.01 cells/mL.
Clinical Performance Study
Aptima Combo 2 Assay (Panther)
The clinical comparability was determined between the predicate AC2 assay and the AC2 RMR assay on the Panther system when evaluating clinical positive and negative specimens. Hologic demonstrated comparability using the AC2 assay as representative of both the ATV and AC2 assays.
Two hundred nineteen (219) remnant clinical swab specimens were evaluated with the predicate AC2 assay and the AC2 RMR assay using two reagent lots of each assay format and across two Panther systems. The predicate AC2 assay was used as the reference result. The positive, negative and overall agreement between the predicate AC2 and AC2 RMR assays were calculated for both CT and GC target interpretations.
| CT Results | AC2 Lyo Result | |||
|---|---|---|---|---|
| Positive | Negative | Total | ||
| PantherAC2 RMRResult | Positive | 39 | 0 | 39 |
| Negative | 0 | 180 | 180 | |
| Total | 39 | 180 | 219 |
Table 5: CT Target Agreement Results
Positive agreement (95% CI) = 100.0% (91.0% - 100.0%) Negative agreement (95% CI) = 100.0% (97.9 - 100.0%) Overall agreement (95% CI) = 100.0% (98.3% - 100.0%)
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| GC Results | AC2 Lyo Result | ||||
|---|---|---|---|---|---|
| Positive | Negative | Total | |||
| PantherAC2 RMRResult | Positive | 48 | 0 | 48 | |
| Negative | 0 | 171 | 171 | ||
| Total | 48 | 171 | 219 |
Table 6: GC Target Agreement Results
Positive agreement (95% CI) = 100.0% (92.6% - 100.0%) Negative agreement (95% CI) = 100.0% (97.8% - 100.0%) Overall agreement (95% CI) = 100.0% (98.3% - 100.0%)
This study demonstrates that the performance of the predicate AC2 assay and AC2 RMR assay is comparable when testing clinical specimens on the Panther system.
Aptima Combo 2 Assay (Tigris)
The clinical comparability was determined between the predicate AC2 assay on the Panther system and the AC2 RMR assay on the Tigris system when evaluating clinical positive and negative specimens. Hologic demonstrated comparability using the AC2 assay as representative of both the ATV and AC2 assays.
Two hundred (200) remnant clinical swab specimens were evaluated with the predicate AC2 assay on Panther and the AC2 RMR assay on Tigris using two reagent lots of each assay format and across two instrument systems. The predicate AC2 assay was used as the reference result. The positive, negative and overall agreement between the predicate AC2 and AC2 RMR assays were calculated for both CT and GC target interpretations.
| AC2 Lyo Result | ||||
|---|---|---|---|---|
| CT Results | Positive | Negative | Total | |
| TIGRISAC2 RMRResult | Positive | 34 | 0 | 34 |
| Negative | 0 | 166 | 166 | |
| Total | 34 | 166 | 200 |
Table 7: CT Target Agreement Results
Positive agreement (95% CI) = 100.0% (89.8% - 100.0%) Negative agreement (95% CI) = 100.0% (97.7% - 100.0%) Overall agreement (95% CI) = 100.0% (98.1% - 100.0%)
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| GC Results | AC2 Lyo Result | |||
|---|---|---|---|---|
| Positive | Negative | Total | ||
| TIGRISAC2 RMRResult | Positive | 47 | 0 | 47 |
| Negative | 0 | 153 | 153 | |
| Total | 47 | 153 | 200 |
Table 8: GC Target Agreement Results
Positive agreement (95% CI) = 100.0% (92.4% - 100.0%) Negative agreement (95% CI) = 100.0% (97.6% - 100.0%) Overall agreement (95% CI) = 100.0% (98.1% - 100.0%)
This study demonstrates that the performance of the predicate AC2 assay and AC2 RMR assay is comparable when testing clinical specimens on the Tigris system.
X. CONCLUSIONS
A comparison of the intended use, technological characteristics, and results from the analytical performance studies demonstrate that the AC2 RMR assay and ATV RMR assay on the Panther and Tigris systems performs comparably to their predicate devices. The results of this evaluation demonstrated that the existing assay performance and claims of the AC2 and ATV assays were not impacted due to the new RMR Probe Reagent.
§ 866.3393 Device to detect nucleic acids from non-viral microorganism(s) causing sexually transmitted infections and associated resistance marker(s).
(a)
Identification. A device to detect nucleic acids from non-viral microorganism(s) causing sexually transmitted infections and associated resistance marker(s) is an in vitro diagnostic device intended for the detection and identification of nucleic acids from non-viral microorganism(s) and their associated resistance markers in clinical specimens collected from patients suspected of sexually transmitted infections. The device is intended to aid in the diagnosis of non-viral sexually transmitted infections in conjunction with other clinical and laboratory data. These devices do not provide confirmation of antibiotic susceptibility since mechanisms of resistance may exist that are not detected by the device.(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 targets the device detects, the results provided to the user, the clinical indications appropriate for test use, and the specific population(s) for which the device is intended.
(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 discussion of the performance characteristics of the device for all claimed specimen types based on analytical studies, including Limit of Detection, inclusivity, cross-reactivity, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, within lab precision, and reproducibility, as appropriate;
(iii) Detailed descriptions of the test procedure, the interpretation of test results for clinical specimens, and acceptance criteria for any quality control testing;
(iv) Limiting statements indicating 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) Reliable 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
(D) If appropriate (
e.g., recommended by the Centers for Disease Control and Prevention, by current well-accepted clinical guidelines, or by published peer reviewed research), that the clinical performance is inferior in a specific clinical subpopulation or for a specific claimed specimen type; and(v) If the device is intended to detect antimicrobial resistance markers, limiting statements, as appropriate, indicating that:
(A) Negative results for claimed resistance markers do not indicate susceptibility of detected microorganisms, as resistance markers not measured by the assay or other potential mechanisms of antibiotic resistance may be present;
(B) Detection of resistance markers cannot be definitively linked to specific microorganisms and the source of a detected resistance marker may be an organism not detected by the assay, including colonizing flora;
(C) Detection of antibiotic resistance markers may not correlate with phenotypic gene expression; and
(D) Therapeutic failure or success cannot be determined based on the assay results, since nucleic acid may persist following appropriate antimicrobial therapy.
(4) Design verification and validation must include:
(i) Detailed device description documentation, including methodology from obtaining sample to result, design of primer/probe sequences, rationale for target sequence selection, and computational path from collected raw data to reported result (
e.g., how collected raw signals are converted into a reported result).(ii) Detailed documentation of analytical studies, including, Limit of Detection, inclusivity, cross-reactivity, microbial interference, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, within lab precision, and reproducibility, as appropriate.
(iii) Detailed documentation and performance results from a clinical study that includes prospective (sequential) samples for each claimed specimen type and, when determined to be appropriate by FDA, additional characterized clinical samples. The study must be performed on a study population consistent with the intended use population and compare the device performance to results obtained from FDA accepted comparator methods. Documentation from the clinical studies must include the clinical study protocol (including a predefined statistical analysis plan) study report, testing results, and results of all statistical analyses.
(iv) A detailed description of the impact of any software, including software applications and hardware-based devices that incorporate software, on the device's functions.