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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 and/or Neisseria gonorrhoeae in clinician-collected endocervical, vaginal and male urethral swab specimens, patientcollected vaginal swab specimens', female and male urine specimens and gynecological specimens collected in the PreservCyt Solution and processed with the Cytyc ThinPrep 2000 System. The assay may be used to test specimens from symptomatic and asymptomatic individuals to aid in the diagnosis of gonococcal and/or chlamydial urogenital disease using the TIGRIS DTS Automated Analyzer or semi-automated instrumentation as specified.

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 and/or Neisseria gonorrhoeae.

This document is an FDA 510(k) clearance letter for an in vitro diagnostic device, not an AI/ML medical device. Therefore, the requested information about acceptance criteria, study design, and performance metrics (especially those related to AI/ML such as multi-reader multi-case studies, human reader improvement with AI, or standalone algorithm performance) is not applicable or cannot be extracted from this document.

The document discusses the substantial equivalence of the TIGRIS® DTS® GEN-PROBE® APTIMA COMOBO 2® Assay to a legally marketed predicate device for the qualitative detection and differentiation of ribosomal RNA from Chlamydia trachomatis and/or Neisseria gonorrhoeae.

Here's the information that can be extracted, noting the limitations related to your AI/ML specific questions:

1. Table of Acceptance Criteria and Reported Device Performance:

This document does not provide a table of quantitative acceptance criteria (e.g., sensitivity, specificity thresholds) or specific performance metrics (e.g., reported sensitivity, specificity values) from a clinical study. It is a clearance letter acknowledging substantial equivalence to a predicate device, not a detailed performance report. Such data would typically be found in the 510(k) submission itself, not the clearance letter.

2. Sample size used for the test set and the data provenance:

• Test set sample size: Not specified in this document.
• Data provenance: Not specified. Clinical studies supporting clearance typically involve multiple sites, which could be domestic or international, and data could be retrospective or prospective. This information is usually detailed in the submission, not the clearance letter.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

This is irrelevant for an in vitro diagnostic assay like the APTIMA COMBO 2 Assay. The "ground truth" for such assays is typically established by reference laboratory methods (e.g., culture, NAATs) or clinical diagnosis, not by human expert interpretation of images or other data. Therefore, there's no concept of "experts establishing ground truth" in the way described for AI/ML imaging devices.

4. Adjudication method for the test set:

Not applicable for an in vitro diagnostic assay. Adjudication methods (like 2+1 or 3+1) are used to resolve disagreements among human readers, typically in image interpretation, which is not the function of this device.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

Not applicable. This is an in vitro diagnostic test for direct pathogen detection, not an AI-assisted diagnostic imaging or decision support system. Therefore, MRMC studies and the concept of human readers improving with AI assistance are irrelevant to this device.

6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:

The device itself is a standalone assay. It performs the detection of rRNA from Chlamydia trachomatis and/or Neisseria gonorrhoeae without human interpretation influencing the result of the assay itself. However, this is not an "algorithm only" in the sense of an AI model; it's a biochemical assay for pathogen identification. The results are typically interpreted by laboratory personnel. Performance studies for such devices evaluate the accuracy of the device's output against a reference standard.

7. The type of ground truth used:

While not explicitly stated in this clearance letter, for in vitro diagnostic assays detecting pathogens, the ground truth is typically established by:

• Culture: For bacterial infections like N. gonorrhoeae.
• Other highly sensitive and specific Nucleic Acid Amplification Tests (NAATs): Often used as a gold standard or "truth" for comparison, especially for C. trachomatis where culture is difficult.
• Clinical diagnosis: Supported by other laboratory findings and patient symptoms.

8. The sample size for the training set:

Not applicable. This document refers to a molecular diagnostic assay, not an AI/ML model that requires a training set. The development of such assays involves analytical studies (assay optimization, limit of detection, cross-reactivity) and clinical studies (evaluating performance on patient samples), but there's no "training set" in the context of machine learning.

9. How the ground truth for the training set was established:

Not applicable, as there is no "training set" in the AI/ML sense for this device. Ground truth in the context of assay development is established through rigorous analytical and clinical validation against established reference methods.

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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) in clinician-collected endocervical, vaginal, and male urethral swab specimens, patientcollected vaginal swab specimens*, and female and male urine specimens. The assay is also intended for use with testing of gynecological specimens collected in the PreservCyt Solution and processed with the Cytyc ThinPrep 2000 System. The assay may be used to test specimens from symptomatic and asymptomatic individuals to aid in the diagnosis of gonococcal and/or chlamydial urogenital disease.

*Patient-collected vaginal swab specimens are an option for screening women when a pelvic exam is not otherwise indicated. The vaginal swab specimen collection kit is not for home use.

The GEN-PROBE® APTIMA® Specimen Transfer Kit is only for use with GEN-PROBE APTIMA assays for the detection of Chlamydia trachomatis and/or Neisseria gonorrhoeae. The GEN-PROBE APTIMA Specimen Transfer Kit allows for APTIMA Assay testing of gynecological specimens collected and processed by the Cytyc ThinPrep 2000 Processor according to the instructions provided.

Clearance of this premarket notification extends the clinical performance claims of the commercially available GEN-PROBE APTIMA Combo 2 Assay to include PreservCyt liquid Pap specimens (collected and processed by the Cytyc ThinPrep 2000 Processor) as acceptable testing specimens. The ancillary kit formulated for this specific application is the GEN-PROBE APTIMA Specimen Transfer Kit. The components of the APTIMA Specimen Transfer Kit include: (1) a transport tube containing transport media with a penetrable cap and (2) specific instructions for use regarding decontamination and specimen processing procedures. The APTIMA Specimen Transfer Kit may only be used in conjunction with GEN-PROBE APTIMA Assays for the detection of Chlamydia trachomatis and/or Neisseria gonorrhoeae..

The GEN-PROBE® APTIMA COMBO2® Assay performance has been evaluated through a multi-center clinical study.

1. Table of Acceptance Criteria and Reported Device Performance

2. Sample size used for the test set and the data provenance:

• Test Set Sample Size: 1,647 female subjects (1,288 asymptomatic, 359 symptomatic).
• Data Provenance: Prospective multi-center clinical study conducted in the United States (as implied by the FDA submission and the company's US address). The study involved subjects attending OB/GYN, family planning, public health, women's, and STD clinics.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

• The document does not explicitly state the number or qualifications of experts used to establish the ground truth. Instead, the ground truth was established by a patient infected status algorithm based on the results of two commercially-available reference NAATs performed on endocervical swab specimens. This implies that the ground truth was determined by laboratory testing protocols rather than direct expert consensus on each individual case.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set:

• Adjudication Method: "None" in the sense of expert human adjudication. The ground truth for the "patient infected status" was based on concordant positive results from two reference NAATs (APTIMA Combo 2 Assay and APTIMA CT Assay for C. trachomatis; APTIMA Combo 2 Assay and APTIMA GC Assay for N. gonorrhoeae). If the two reference NAATs disagreed or were negative, the patient was designated as non-infected. This is a form of algorithmic adjudication rather than human expert adjudication.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

• No, a multi-reader multi-case (MRMC) comparative effectiveness study was NOT done. This study evaluates a laboratory diagnostic assay (APTIMA Combo 2 Assay) and does not involve human readers interpreting images or data to be assisted by AI. Therefore, the concept of "human readers improve with AI vs without AI assistance" does not apply here.

6. If a standalone (i.e. algorithm only without human-in-the loop performance) was done:

• Yes, this was effectively a standalone performance study for the device. The APTIMA Combo 2 Assay, as a nucleic acid amplification test, functions as an algorithm-only device (an in vitro diagnostic test kit that produces a qualitative result based on amplification and detection of rRNA). Its performance was evaluated against a defined ground truth without direct human interpretation in a diagnostic loop that would affect its result. The assay generates a direct qualitative result (positive/negative) which is then used by clinicians for diagnosis.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):

• Algorithm-based Patient Infected Status (Reference NAATs):
  • For C. trachomatis: A patient was considered infected if both the APTIMA Combo 2 Assay and the APTIMA CT Assay (both performed on endocervical swabs) returned positive results.
  • For N. gonorrhoeae: A patient was considered infected if both the APTIMA Combo 2 Assay and the APTIMA GC Assay (both performed on endocervical swabs) returned positive results.
  • A non-infected patient was established if the results from the two reference NAATs disagreed or were negative. This is effectively a composite reference standard based on other validated diagnostic tests.

8. The sample size for the training set:

• The document does not explicitly describe a separate training set for the APTIMA Combo 2 Assay in the context of this submission. The product being submitted for clearance is an existing assay (APTIMA Combo 2 Assay (K003395)) and the clearance sought is an extension of its clinical performance claims to include PreservCyt liquid Pap specimens.
• The non-clinical (analytical) studies (Limit of Detection, Specificity, Interference, Recovery, Stability, Precision) likely involved internal development and optimization, which could be considered an implicit "training" or development phase. However, a distinct "training set" in the machine learning sense is not mentioned. The clinical study described is solely for validation/testing of the assay's performance with the new specimen type.

9. How the ground truth for the training set was established:

• As a distinct training set is not explicitly mentioned for this 510(k) submission, the method for establishing its ground truth is also not detailed. The ground truth for the non-clinical (analytical) studies typically involved controlled laboratory experiments using known concentrations of organisms and interference substances, with results verified by standard laboratory methods.

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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 ribonucleic acid (rRNA) from Chlamydia trachomatis and/or Neisseria gonorrhoeae in clinician-collected endocervical, vaginal, and male urethral swab specimens, patient-collected vaginal swab specimens* and male and female urine specimens. The assay may be used to test specimens from symptomatic and asymptomatic individuals to aid in the diagnosis of gonococcal and/or chlamydial urogenital disease.

*Patient-collected vaginal swab specimens are an option for screening women when a pelvic exam is not otherwise indicated. The vaginal swab specimen collection kit is not for home use.

The APTIMA Vaginal Swab Specimen Collection Kit is for use with the APTIMA Assays for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae. The APTIMA Vaginal Swab Specimen Collection Kit is intended to be used for clinician and patient collection of vaginal swab specimens according to the instructions provided. Patient-collected vaginal swab specimens are an option for screening women when a pelvic exam is not otherwise indicated. The APTIMA Vaginal Swab Specimen Collection Kit is not for home use.

Clearance of this premarket notification extends the clinical performance claims of the commercially available GEN-PROBE APTIMA Combo 2 Assay to include clinician-collected and patient-collected vaginal swabs (in a medical setting) as acceptable testing specimens. The ancillary kit formulated for this specific application is the GEN-PROBE APTIMA Vaginal Swab Specimen Collection Kit. The components of the APTIMA Vaginal Swab Specimen Collection Kit include: (1) a sterile swab for the collection of vaginal specimens and (2) a transport tube containing transport media with a penetrable cap.

The APTIMA Vaginal Swab Specimen Collection Kit is for use with the APTIMA Assays for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae. The APTIMA Vaginal Swab Specimen Collection Kit is intended to be used for clinician and patient collection of vaginal swab specimens according to the instructions provided. The APTIMA Vaginal Swab Specimen Collection Kit not for home use.

The APTIMA Combo 2 Assay incorporates the technologies of target capture, in vitro nucleic acid amplification, and hybridization of target amplicons with acridinium ester-labeled DNA probes to specifically detect and differentiate both C. trachomatis and N. gonorrhoeae nucleic acids in clinical specimens. GEN-PROBE's proprietary technologies are combined in this product to allow qualitative detection of C. trachomatis rRNA and N. gonorrhoeae rRNA.

Here's a breakdown of the acceptance criteria and study details for the GEN-PROBE® APTIMA® Combo 2 Assay, based on the provided text:

1. Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied through the sensitivity and specificity values reported, which are compared against a "patient infected status algorithm" as the ground truth. While explicit numerical acceptance thresholds are not stated in the provided text (common in older 510(k) summaries which often relied on substantial equivalence to predicate devices), the study aims to demonstrate high performance.

Chlamydia trachomatis (CT)

Neisseria gonorrhoeae (NG)

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

The study was a multi-center clinical study involving 1,464 symptomatic and asymptomatic female subjects.

• Sample Size:
  • For CT analysis: 2,868 vaginal swab test results.
  • For NG analysis: 2,867 vaginal swab test results.
  • These numbers represent the combined results from patient-collected and clinician-collected vaginal swabs.
• Data Provenance: The data was collected from subjects attending STD, OB/GYN, teen, and family planning clinics. The text does not explicitly state the country of origin, but given it's a US FDA submission, it's highly likely to be a prospective multi-center clinical study conducted in the United States.

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

The ground truth was established using an algorithm, not directly by human experts interpreting images or test results. Therefore, the concept of "number of experts" and "qualifications of those experts" as typically applied to expert review in imaging studies, does not directly apply here. The accuracy of the reference standard relies on the performance of the commercially available NAATs used.

4. Adjudication Method for the Test Set

The adjudication method for establishing the patient infected status was algorithmic (rule-based):

• Subjects were considered infected with C. trachomatis or N. gonorrhoeae if two of the four reference NAAT results were positive (one specimen testing positive in each NAAT: APTIMA Combo 2 Assay and another commercially available NAAT, using endocervical swab and urine specimens).
• Subjects were considered non-infected if less than two reference NAAT results were positive.

This method uses concordant results from multiple tests/specimens to define the "true" infection status.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not performed. This study is for an in vitro diagnostic (IVD) assay detecting biomarkers, not an AI-assisted diagnostic imaging device that involves human reader interpretation. Therefore, the concept of human readers improving with AI vs. without AI assistance does not apply.

6. Standalone Performance Study

Yes, a standalone performance study was done for the algorithm (the APTIMA Combo 2 Assay). The entire clinical study described evaluates the performance of the device on its own, comparing its results from vaginal swab specimens to the defined patient infected status algorithm. The reported sensitivity and specificity values are for the device operating as a standalone diagnostic tool for vaginal swab specimens.

7. Type of Ground Truth Used

The ground truth used was an algorithmic consensus based on multiple reference nucleic acid amplification tests (NAATs). Specifically:

• Endocervical swab and urine specimen results from the commercially-available APTIMA Combo 2 Assay and another commercially-available NAAT were used.
• Infection status was determined by requiring a positive result from both reference NAATs.
• Culture was not used as a reference test for this specific study, as the APTIMA Combo 2 Assay had previously been evaluated against culture for other specimen types (as per K003395).

8. Sample Size for the Training Set

The document does not provide information regarding a distinct "training set" sample size. For an IVD assay like this, development typically involves analytical validation (sensitivity, specificity, interference etc.) and then clinical validation with a distinct set of clinical samples. The analytical studies (like analytical sensitivity, specificity, recovery, interference) might be considered analogous to early-stage development/testing, but a formal "training set" in the machine learning sense is not explicitly mentioned or typically applicable for this type of assay in this context. The clinical study described served as the primary performance evaluation.

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

As noted above, the concept of a separate "training set" with established ground truth in the machine learning context is not detailed. The primary clinical study used the algorithmic consensus described in point 4 as its ground truth for evaluating the device's performance.

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The GEN-PROBE® APTIMA® Adapter Kit is to be used to test male urethral specimens collected with the GEN-PROBE® PACE® Specimen Collection Kit for Urethral or Conjunctival Specimens or female endocervical specimens collected with the GEN-PROBE PACE Specimen Collection Kit for Endocervical Specimens in the APTIMA Assays.

The APTIMA Adapter Kit is specifically formulated to allow testing of specimens collected with the GEN-PROBE PACE collection devices in the APTIMA Combo 2 Assay. The APTIMA Adapter Kit provides a diluent for PACE specimens. The diluent is identical to the transport media provided in both the PACE and APTIMA collection kits. The APTIMA Adapter Kit can only be used in conjunction with the GEN-PROBE PACE Specimen Collection Kits for testing in the APTIMA Combo 2 Assay. The description provided pertains to the test application (the APTIMA Combo 2 Assay).

Here's a breakdown of the acceptance criteria and study details for the GEN-PROBE® APTIMA® Adapter Kit, based on the provided document:

Acceptance Criteria and Device Performance

The study aimed to establish the equivalence of the APTIMA Adapter Kit with the APTIMA Combo 2 Unisex Swab Collection Kit. While explicit "acceptance criteria" in terms of specific percentages were not stated before the results, the implication is that high levels of agreement between the two methods would demonstrate equivalence.

The study concluded that the results demonstrate that using the APTIMA Adapter Kit with specimens collected in the PACE Specimen Collection Kits yield equivalent APTIMA Combo 2 Assay results when compared to specimens collected with the APTIMA Combo 2 Assay, Unisex Swab Specimen Collection Kits. This statement confirms the device met the implicit acceptance criteria of demonstrating equivalence.

Study Details

1. Sample sizes used for the test set and data provenance:

• Male subjects: 154
• Female subjects: 232
• Total test results analyzed: 772 (for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC))
• Data Provenance: The specimens were collected from subjects attending STD and Family Planning clinics. The document does not explicitly state the country of origin, but given the submission is to the FDA (USA), it is highly probable the data is from the USA. The study design comparing two collection methods for the same patients suggests a prospective collection for this specific study, although the underlying APTIMA Combo 2 Assay itself would have been validated with clinical data (which could be retrospective). This specific study focuses on the adapter kit's performance in a comparative manner.

2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

• The document does not mention the number of experts or their qualifications used to establish ground truth. This is a study comparing two specimen collection methods with the same assay, rather than comparing an assay to a gold standard. The "ground truth" implicitly relies on the established accuracy of the APTIMA Combo 2 Assay itself.

3. Adjudication method (e.g. 2+1, 3+1, none) for the test set:

• The document does not describe any adjudication method. The study design compares results from paired swab specimens using two different collection kits with the same assay.

4. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, if so, what was the effect size of how much human readers improve with AI vs without AI assistance:

• No. This is not an AI or imaging device, nor is it a multi-reader study. The device is an adapter kit for a diagnostic assay.

5. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:

• Yes, in essence. The APTIMA Combo 2 Assay itself, with the adapter kit, operates as a standalone diagnostic test for detecting C. trachomatis and N. gonorrhoeae rRNA. The "algorithm" here refers to the assay's biochemical processes and detection methods (TMA and DKA), which yield qualitative results (positive/negative) without human interpretation of raw data beyond reading the instrument's output. The study here validates the specimen collection component in conjunction with this standalone assay.

6. The type of ground truth used (expert consensus, pathology, outcome data, etc):

• The "ground truth" in this comparative study is the results obtained from specimens collected with the APTIMA Combo 2 Unisex Swab Collection Kit. The study aims to show that using the PACE kit with the adapter yields equivalent results to this existing, presumably validated, collection method. The underlying ground truth for the APTIMA Combo 2 Assay itself would likely be a combination of culture results (historically considered the gold standard for N. gonorrhoeae), and molecular methods, as culture is no longer the gold standard for C. trachomatis. The document mentions amplification methods (like APTIMA Combo 2) are more sensitive than culture for C. trachomatis.

7. The sample size for the training set:

• The document does not provide information about a separate training set. This kit adapts an existing, validated assay. The study cited is a clinical validation study for the adapter kit's use with the existing assay.

8. How the ground truth for the training set was established:

• As no training set is mentioned for this specific adapter kit validation, this information is not available in the document.

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