(28 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, vaginal, throat, rectal, and male urethral swab specimens, clinician-collected gynecological specimens collected in the PreservCyt® Solution, patient-collected vaginal swab specimens,1 and female and male urine specimens.
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 or semi-automated instrumentation as specified. 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 specimens1; 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.
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 clearance of this Special 510(k) application will allow the use of a Ready-Made Reagent format for the Aptima Combo 2 assay (AC2) and the Aptima Trichomonas Vaginalis assay (ATV) on the Tigris and Panther systems. The use of Ready-Made Reagent assays does not change the principles of procedure, intended use, or primary technological characteristics.
Currently, each of the AC2 and ATV Amplification, Enzyme, and Probe reagents are provided in two parts: a lyophilized reagent (cake form) and a reconstitution solution (liquid form). Per the instructions provided in the respective assay's package inserts, the customers are instructed to prepare the reagents by reconstituting each reagent by combining the bottles of lyophilized reagent with the reconstitution solution and mixing reagents manually prior to placing on the Panther or Tigris system. Hologic developed "Ready Made Reagents" (RMRs), which are liquid format or pre-reconstituted Amplification, Enzyme, and Probe reagents available for customers to procure in the 250-Test Kit size available for use on both the Tigris and Panther systems.
Changes to the user interface are minimal as the RMRs are identical to the lyophilized reagents once they have been reconstituted at the laboratory. In order to prepare the current format reagents (lyophilized format), the laboratory personnel pairs each reconstitution solution (Amplification, Enzyme, and Probe) with its respective lyophilized reagent. Using the RMR format, the customer eliminates the reconstitution step and is only required to bring the three reagents to room temperature following the same process currently done for the previously reconstituted reagents. All subsequent steps by the operator are unchanged. All assay principles and processing steps on the Panther or Tigris systems remain unchanged. There are no changes to the instrument hardware or software based on this change.
The provided text describes a 510(k) summary for new "Ready-Made Reagents" (RMRs) for the Aptima Combo 2 Assay and Aptima Trichomonas Vaginalis Assay, designed to simplify reagent preparation for laboratory personnel. The submission aims to demonstrate substantial equivalence to previously cleared predicate devices.
Here's an analysis of the acceptance criteria and study proving the device meets them, based on the provided document:
1. Table of Acceptance Criteria and Reported Device Performance
The document doesn't explicitly state "acceptance criteria" in a numerical table format with pre-defined thresholds. However, the implicit acceptance criteria for demonstrating substantial equivalence are based on comparability to the predicate devices, particularly in the analytical performance studies (Limit of Detection and Intended Use) and clinical performance studies. The goal is to show that the RMR format performs equivalently to the existing lyophilized format.
Implicit Acceptance Criteria (based on study design and conclusions):
| Criterion Type | Specific Criterion (Implied) | Reported Device Performance (AC2 RMR vs. Current AC2 on Panther) | Reported Device Performance (AC2 RMR vs. Current AC2 on Tigris) | Reported Device Performance (ATV RMR vs. Current ATV on Panther) | Reported Device Performance (ATV RMR vs. Current ATV on Tigris) |
|---|---|---|---|---|---|
| Intended Use Study | 100% agreement between RMR format and current format for negative, positive, and dual positive panels based on expected positivity. | 100% agreement | 100% agreement | 100% agreement | 100% agreement |
| Limit of Detection | LoD for RMR assay determined to be within ½ log of the LoD for the current assay, with ≥95% positivity at the lowest concentration equivalent to the current assay. | CT: 0.01 IFU/mL (equivalent to current) | |||
| GC: 0.1 cells/mL (equivalent to current) | CT: 0.01 IFU/mL (equivalent to current) | ||||
| GC: 0.1 cells/mL (equivalent to current) | 0.003 TV/mL (equivalent to current) | 0.01 TV/mL (within ½ log of 0.003 TV/mL) | |||
| Clinical Performance | High positive, negative, and overall agreement between RMR format and current format when testing clinical specimens (for AC2 on Panther, used as general representative). | CT: Positive Agreement 100%, Negative Agreement 99.6%, Overall Agreement 99.7% | |||
| GC: Positive Agreement 100%, Negative Agreement 99.6%, Overall Agreement 99.7% | Not explicitly stated but implied comparable based on AC2 Panther results generalizability | Not explicitly stated but implied comparable based on AC2 Panther results generalizability | Not explicitly stated but implied comparable based on AC2 Panther results generalizability |
2. Sample Size Used for the Test Set and Data Provenance
- Intended Use Study:
- The document mentions "negative and positive panels" and "CT positive, GC positive, and CT/GC dual positive panels" but does not specify the exact number of samples/panels used for each test.
- Data provenance is implicitly laboratory-generated (panels with known analytes), not clinical patient samples for this specific study section.
- Limit of Detection Study:
- The document mentions using "stocks of CT and GC organisms in negative clinical liquid pap specimens" and "stocks of TV organisms in negative clinical liquid pap specimens".
- Does not specify a sample size (number of specimens/replicates) explicitly for the LoD determination.
- Data provenance appears to be laboratory-prepared samples using clinical specimen matrices.
- Clinical Performance Study:
- Sample Size: Three hundred (300) remnant clinical swab specimens.
- Data Provenance: Retrospective, clinical samples ("remnant clinical swab specimens"). The country of origin is not specified but implicitly within the US as this is an FDA submission.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
- Not applicable in the traditional sense of image-based AI studies using human expert consensus.
- For these in vitro diagnostic (IVD) assays, the "ground truth" for the analytical and clinical studies is established through:
- Known concentrations in prepared panels (Intended Use, LoD).
- Reference assay results (the "current AC2 assay" or "current ATV assay" is used as the baseline/reference result in the clinical comparability study). This assumes the predicate device's performance is the established truth for comparison.
4. Adjudication Method for the Test Set
- Not applicable in the context of human expert adjudication for a test set.
- The "adjudication" is essentially the comparison of the RMR assay results against the predicate assay results or against known panel concentrations. Discrepancies would be investigated, but there's no mention of a multi-reader/adjudicator process.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done
- No, an MRMC comparative effectiveness study was not done. This type of study is more common for imaging AI devices where human readers interpret images with and without AI assistance.
- This submission is for an in vitro diagnostic (IVD) assay where the device output is typically a qualitative (positive/negative) or quantitative result, not an interpretation by a human reader that is then augmented by AI. The comparison is directly between the new reagent format and the existing reagent format.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done
- Yes, in spirit, the studies are analogous to standalone performance. The performance evaluation of the RMR assays (the "device") is measured directly against established analytical and clinical benchmarks (predicate assay performance, known concentrations). There isn't a human-in-the-loop component for the performance evaluation of the assay itself, beyond the manual steps involved in sample preparation or loading described in the "Differences" section. The assay's output (presence/absence of target RNA) is the direct result.
7. The Type of Ground Truth Used
- Analytical Truth: Known concentrations of target organisms in prepared panels (for Intended Use and Limit of Detection studies).
- Comparative Truth: The previously cleared predicate devices (Aptima Combo 2 Assay and Aptima Trichomonas Vaginalis Assay using the lyophilized reagent format) served as the "reference result" or "baseline" for comparison in both analytical and clinical studies. This is a common approach in 510(k) submissions for modifications to existing devices.
8. The Sample Size for the Training Set
- Not applicable. This submission is for a modification to an existing IVD assay (a change in reagent format), not for a machine learning or AI algorithm that requires a "training set." The assays are nucleic acid amplification tests (NAATs) based on established biochemical principles, not on learned patterns from a dataset.
9. How the Ground Truth for the Training Set was Established
- Not applicable as there is no training set for this type of device.
§ 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.