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The RNARetain® device is a single-use, prefilled container intended for the collection, storage, and transportation of fresh breast tissue specimens for subsequent RNA isolation and further molecular diagnostic testing. For Professional Use Only.

The RNARetain® device consists of an aqueous, hypertonic tissue preservation solution that is provided in a single-use, non-sterile vial intended to serve as the container for the collection, storage, and transport of breast tissue specimens. The ability of the solution formulation to preserve fresh tissue and nucleic acids within the tissue is due to its rapid permeation of tissue to protect cellular nucleic acids from nucleases that would otherwise rapidly degrade the nucleic acids within the specimen. The demonstrated inhibitory effect of the RNARetain® solution on the growth of bacteria, yeast and mold protects the specimen from inadvertent microbial contamination during storage or usage of the device.

The RNARetain® device is a single-use, prefilled container intended for the collection, storage, and transportation of fresh breast tissue specimens for subsequent RNA isolation and further molecular diagnostic testing. The device's performance was evaluated through several non-clinical analytical studies, including precision/reproducibility, stability of MammaPrint® outcomes, comparison with a predicate device, and internal analytical performance by Asuragen.

1. Table of Acceptance Criteria and Reported Device Performance:

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

• Reproducibility (K070675): 5 tumor samples, each isolated in duplicate (total 10 isolations). Origin: Not explicitly stated, but part of Agendia's MammaPrint® submission. Retrospective.
• Stability of MammaPrint® outcomes in RNARetain® (K070675): One tumor, with sections preserved in RNARetain® and immediately snap-frozen. Both sections were labeled 5 times. Origin: Not explicitly stated, but part of Agendia's MammaPrint® submission. Retrospective.
• Comparison Studies (K070675):
  • RNARetain® vs. snap-frozen: 33 breast tumor samples. One part of each sample stored in RNARetain®, another part snap-frozen. Origin: Collected in 2003 as a pilot study for the Dutch Raster clinical trial. Retrospective.
  • Frozen vs. frozen: 18 tumors, with two parts of each immediately snap-frozen. Origin: Collected in the same time period as the 33 breast tumor samples. Retrospective.
• Repeatability and Reproducibility (Asuragen): 10 adjacent pairs of breast tissue from 3 subjects (total 30 tissue samples). Origin: Asuragen, within the US. Prospective (implied, as it was specifically collected for this study).
• Sample Stability (Asuragen for storage conditions): Human breast cancer cell line MCF-7. Quantitative sample size for each condition not explicitly stated (e.g., how many replicates per condition), but various time points and temperatures were tested. Origin: Asuragen labs.
• RNARetain® Reagent Stability: 3 lots of the 8mL vial (6 mL volume); unspecified number of lots for 6 mL vial (5 mL volume) and 2 mL vial (1 mL volume). Origin: Asuragen.

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

• Comparison Studies (K070675): "HE stained sections were re-examined by a pathologist to confirm invasive ductal carcinoma and sufficient tumor cell content." Specific number and qualifications of pathologists are not given beyond "a pathologist".

4. Adjudication Method for the Test Set:

• Not applicable as the reported studies primarily involve analytical performance metrics (RNA purity, integrity, yield, MammaPrint® index correlation) rather than subjective assessments by multiple readers.

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 MRMC comparative effectiveness study was done. This device is a pre-analytical system for tissue preservation, not an AI diagnostic tool that assists human readers.

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

• Yes, the performance studies described are essentially standalone analytical performance evaluations of the RNARetain® device's ability to preserve RNA, mimicking the "algorithm only" concept in the context of a pre-analytical device. The device's performance is measured directly through RNA metrics and comparison to a gold standard (flash-frozen tissue) or established assay (MammaPrint®).

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.):

• MammaPrint® Index: The MammaPrint® assay itself serves as a reference, with the "original index" used for reproducibility studies (Table 3), implying an established ground truth for those samples.
• Pathology: For tissue samples in the comparison studies, "HE stained sections were re-examined by a pathologist to confirm invasive ductal carcinoma and sufficient tumor cell content." This indicates pathology review was used to establish the suitability of the tissue samples.
• Reference Methods: The "gold standard" for tissue preservation (flash-frozen tissue) was used as a comparator/ground truth for RNA yield, purity, and integrity measurements. Fresh Frozen cells were used as a comparator for sample stability studies.

8. The Sample Size for the Training Set:

• Information on a separate "training set" for the RNARetain® device, in the context of an algorithm or learnable system, is not applicable. RNARetain® is a chemical preservation solution and does not involve AI or machine learning that would require a distinct training set. The studies described are validation studies of its chemical and physical performance.

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

• Not applicable, as there is no training set in the context of an AI/ML algorithm for this device.

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The PAXgene™ Blood RNA System consists of a blood collection tube (PAXgene™ Blood RNA Tube) and nucleic acid purification kit (PAXgene™ Blood RNA Kit). It is intended for the collection, storage, and transport of blood and stabilization of intracellular RNA in a closed tube and subsequent isolation and purification of host RNA from whole blood for RT-PCR used in molecular diagnostic testing.

Performance characteristics for the PAXgene™ Blood RNA System have only been established with "cfos and IL1B." The user is responsible for establishing appropriate PAXgene™ Blood RNA System performance characteristics for other target transcripts.

PAXgene Blood RNA Kit is for the purification of intracellular RNA from whole blood collected in the PAXgene Blood RNA Tube. When the kit is used in conjunction with the PAXgene Blood RNA Tube, the system provides purified intracellular RNA from whole blood for RT-PCR used in molecular diagnostic testing.

Performance characteristics for the PAXgene Blood RNA System have only been established with FOS and IL1B gene transcripts. The user is responsible for establishing appropriate PAXgene Blood RNA System performance characteristics for other target transcripts.

The PAXgene™ Blood RNA System consists of:

• PAXgene™ Blood RNA tubes
• · PAXgene™ Blood RNA kit.

The PAXgene™ Blood RNA tube is of a sterile, plastic, evacuated blood collection tube containing stabilization solution (tetradecyl trimethyl-ammonium oxalate and tartaric acid. These components serve to lyse cells, protect RNA molecules from degradation by ribonucleases (RNases) and prevent induction of gene expression. The kit consists of 5 aqueous buffer solutions for resuspending, binding, washing, and eluting RNA, RNase-free water, proteinase K. an RNase-Free DNase set, spin columns, microcentrifuge tubes, processing tubes, and secondary blood collection tube closures.

Here's an analysis of the provided text regarding the PAXgene™ Blood RNA System, focusing on the acceptance criteria and the study proving it, as per your requested format:

1. Table of Acceptance Criteria and Reported Device Performance

The provided 510(k) summary (K082150) does not explicitly state quantitative acceptance criteria or detailed device performance metrics in a readily extractable table format. Instead, it focuses on demonstrating substantial equivalence to a predicate device (K042613) by showing that the RNA obtained using the updated system (with QIAcube automation) is "compatible with molecular diagnostic applications such as mRNA transcript level determination by RT-PCR."

The core assertion is: "Therefore the processing of RNA by the automated protocol on QIAGEN's QIAcube is equivalent to the manual process as described in K042613."

Implicit Acceptance Criteria (derived from the justification of equivalence):

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

The document does not specify the sample size used for the test set or the data provenance (e.g., country of origin, retrospective or prospective nature of the data). The information provided is very high-level, stating only that "Design Control activities performed demonstrated the RNA obtained from the QIAcube is compatible..." This suggests an internal validation study, but no details on the participants or samples are given.

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

This information is not provided in the document. The study described is a technical validation of RNA compatibility, not a diagnostic study requiring expert consensus on clinical ground truth.

4. Adjudication Method for the Test Set

This information is not applicable/not provided as the study did not involve human interpretation or a "test set" in the sense of comparing human reads or diagnostic outcomes. It was an analytical performance study.

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

A Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This type of study is more relevant for diagnostic imaging or interpretation where different readers evaluate cases. The PAXgene™ Blood RNA System is a pre-analytical device for RNA purification.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

The study described could be considered a form of "standalone" evaluation in that it evaluates the automated RNA purification process (the "algorithm" or automated protocol) on QIAGEN's QIAcube in isolation, without involving human interpretation of the purification process itself. However, "standalone" usually refers to the performance of a diagnostic algorithm independent of human input in the diagnostic decision. Here, the "performance" is the quality and yield of the RNA. The document focuses on demonstrating that the RNA produced by the automated system is equivalent to that produced by the manual system of the predicate device, for subsequent molecular diagnostic testing.

7. Type of Ground Truth Used

The "ground truth" in this context is the quality and quantity of RNA deemed acceptable for downstream molecular diagnostic applications, specifically RT-PCR, as well as the equivalence to the RNA produced by the predicate manual method. This is established through the "Design Control activities" and presumably involved analytical measurements (e.g., RNA yield, purity, integrity, and successful amplification of target transcripts like cfos and IL1B). It is an analytical validation against established laboratory standards and the performance of the predicate.

8. Sample Size for the Training Set

This information is not applicable/not provided. The PAXgene™ Blood RNA System is a chemical and mechanical system for RNA purification; it does not involve machine learning or AI models that require a "training set" in the conventional sense. The "training" here would be the development and optimization of the automated protocol itself.

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

This information is not applicable/not provided for the same reasons as point 8. The "ground truth" for developing the automated protocol would have been achieving optimal RNA quality and yield comparable to the manual method, established through iterative testing and analytical measurements.

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The PAXgene™ Blood RNA System consists of a blood collection tube (PAXgene™ Blood RNA Tube) and nucleic acid purification kit (PAXgene™ Blood RNA Kit). It is intended for the collection, storage, and transport of blood and stabilization of intracellular RNA in a closed tube and subsequent isolation and purification of host RNA from whole blood for RT-PCR used in molecular diagnostic testing.

Performance characteristics for the PAXgene™ Blood RNA System have only been established with "cfos and IL1B." The user is responsible for establishing appropriate PAXgene™ Blood RNA System performance characteristics for other target transcripts.

The PAXgene™ Blood RNA System consists of:

• the PAXgene™ Blood RNA tubes and .
• the PAXgene™ Blood RNA kit. .

The PAXgene™ Blood RNA tube is of a sterile, plastic, evacuated blood collection tube containing stabilization solution (tetradecyl trimethyl-ammonium oxalate and tartaric acid. These components serve to lyse cells, protect RNA molecules from degradation by ribonucleases (RNases) and prevent induction of gene expression.

The kit consists of 5 aqueous buffer solutions for resuspending, binding, washing, and eluting RNA, RNase-free water, proteinase K, an RNase-Free DNase set, spin columns, microcentrifuge tubes, processing tubes, and secondary blood collection tube closures.

The provided text details the performance characteristics and studies for the PAXgene™ Blood RNA System, intended for the collection, storage, and purification of intracellular RNA from whole blood for RT-PCR.

1. Table of Acceptance Criteria and Reported Device Performance

• Repeatability (quadruplicate per donor pool, per lot/user): Min/max % CV 3.4-28.8, overall 11.9%
• Reproducibility (per user, between lots): Min/max % CV 8.7-20.1, overall 14.9%
• Reproducibility (between lots and users): Min/max % CV 8.7-23.1, overall 16.4% |
  | PAXgene Tube Stability (25°C) | Draw volume, liquid additive volume, closure performance, pH, conductivity, density, RNA yield, purity, CFOS/18S rRNA & IL1B/18S rRNA stability | All physical/chemical attributes and functional performance were within expected ranges for 6 months (sponsor claims 19 months based on accelerated studies) |
  | PAXgene Kit Component Stability | Recovery of input RNA, variability of recovery, degree of inhibition, pH, conductivity, density, Proteinase K & DNase I activity, bioburden | All parameters in expected ranges for 6 months real-time storage; no bioburden; acceptable performance after extreme temperature simulation |
  | RNA In Situ Stability (various temperatures/times/freeze-thaw) | RNA yield, purity, integrity (CFOS/18S rRNA, IL1B/18S rRNA) within acceptance range | All samples at all time points, temperatures, and freeze/thaw cycles were within the acceptance range (with one unspecified exception) |
  | Linearity/Reportable Range (CFOS) | 0.2 to 7.8 ng total input nucleic acid; up to 25% DNA without affecting performance | Met |
  | Linearity/Reportable Range (IL1B) | 0.1 to 7.8 ng total input nucleic acid; up to 5% DNA without affecting performance | Met |

2. Sample Sizes and Data Provenance

• Test Set (Precision/Reproducibility of RT-PCR Assays):
  • K2EDTA samples: 5 donors, 5 tubes/donor (25 tubes total), 10 ml blood/tube. RNA isolated via OIAzol and RNeasy, pooled, concentrated.
  • PAXgene samples: 48 donors, 8 tubes/donor (384 PAXgene tubes total), 2.5 ml blood/tube. RNA purified, DNase treated, concentrated, pooled.
  • Reproducibility Design: 3 different component lots, 3 different experimenters, 3 different laboratories (equipment), on 3 different days.
    • Each "run" (9 runs total) involved: 2 RNA samples (K=calibrator, T=test), each with 10 replicates. This generated 180 ΔCT values and 90 ΔΔCT values.
• Test Set (Precision/Reproducibility of PAXgene Blood RNA System - Experiment 1):
  • 14 donors (WBC: 4.8-11.0 x 10^6 cells/ml blood)
  • 12 tubes/donor (168 PAXgene tubes total)
• Test Set (Precision/Reproducibility of PAXgene Blood RNA System - Experiment 2):
  • 30 donors (WBC: 4.8-11.0 x 10^6 cells/ml blood)
  • 12 tubes/donor (360 PAXgene tubes total)
  • Blood from 3 donors pooled and aliquoted into empty tubes to create 10 donor pools with 36 tubes each.
• Test Set (RNA Purity, DNA Contamination, RNA Yield):
  • 10 donors
  • 2 PAXgene tubes/donor (20 tubes total) + 1 EDTA tube/donor (10 EDTA tubes) for WBC count.
• Test Set (RT-PCR Inhibition):
  • 22 blank eluates from columns.
  • HeLa cell RNA used as template.
• Test Set (PAXgene Tube Stability):
  • Functional tests: 60 tubes/time point (TTP) for accelerated studies (120 tubes total), 60 tubes/TTP for real-time study (810 tubes scheduled, 6 months data presented).
  • Functional performance: 10 donors per time point for RNA yield, purity, CFOS/IL1B relative levels (3 time points for blood-filled tubes storage at 18-25°C x 2 preparations = 60 measurements).
• Test Set (PAXgene Kit Component Stability):
  • Two reagent sets per time point for functional stability (4 blank eluates, 8 RNA eluates).
• Test Set (RNA In Situ Stability):
  • Multiple experiments with 10 donors each. Number of PAXgene tubes per donor varied (6, 10, 12, 14 tubes/donor), resulting in totals of 60, 100, 120, and 140 tubes for different conditions.
• Data Provenance: The studies appear to be prospective, performed by the applicant (PreAnalytiX GmbH) to demonstrate the device's performance. The applicant is based in Switzerland (GmbH). The data is generated in a lab setting, not clinical real-world data from multiple countries.

3. Number of Experts and Qualifications for Ground Truth

The document does not mention the use of experts to establish a ground truth for the "test set" in the context of diagnostic interpretation (e.g., radiologists evaluating images). This device is a sample collection and purification system, not an interpretative diagnostic device. The ground truth for its performance is instead based on quantitative measurements of RNA yield, purity, integrity, and the absence of inhibitors. These are objective measures determined by laboratory instrumentation (e.g., spectrophotometers, Q-RT-PCR machines, BioAnalyzer).

However, "experimenters" and "technicians" are mentioned:

• Precision/Reproducibility of O-RT-PCR Duplex Assays: "3 different experimenters"
• Precision/Reproducibility of PAXgene Blood RNA System (both Experiments 1 & 2): "3 technicians"

Their specific qualifications (e.g., years of experience) are not provided, but they are implied to be trained laboratory personnel.

4. Adjudication Method

Not applicable. The "ground truth" for this device is based on objective, quantifiable laboratory measurements (e.g., RNA yield, purity ratios, Ct values), not on subjective expert interpretation requiring adjudication.

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

No. An MRMC comparative effectiveness study is not applicable for this type of device (RNA collection and purification system). Such studies are typically used for diagnostic imaging or interpreted assays where human readers are involved in making diagnostic decisions, and the AI aims to assist or replace them. This device is a sample preparation tool, and its "performance" is measured analytically, not by human reader accuracy.

6. Standalone (Algorithm Only) Performance

Yes, the studies described are essentially "standalone" performance evaluations of the device and its components. The PAXgene Blood RNA System's analytical performance (e.g., RNA yield, purity, integrity) is assessed directly through laboratory assays, without human intervention in the "decision-making" loop. Its function is to prepare RNA for downstream molecular diagnostic testing (RT-PCR), meaning its performance is evaluated on its ability to produce high-quality RNA suitable for such assays. The Q-RT-PCR assays run on the RNA extracted by the system are designed to evaluate the RNA quality produced by the device, not to perform a diagnosis.

7. Type of Ground Truth Used

The ground truth used is primarily based on analytical measurements derived from standard laboratory techniques:

• Spectrophotometric measurements: Absorbance at 260 nm (for RNA yield), A260/A280 ratio (for RNA purity).
• Quantitative Reverse Transcription-Polymerase Chain Reaction (Q-RT-PCR) assays: Using CFOS and IL1B transcripts normalized to 18S rRNA (for RNA integrity and relative transcription levels). This involves comparing threshold cycle (Ct) values.
• Electropherograms (BioAnalyzer): For RNA purity and integrity.
• Beta-actin PCR: To determine genomic DNA contamination.
• Biological assays: Proteinase K and DNase I activity tests.
• Physical and chemical property tests: pH, conductivity, density, draw volume, liquid additive volume, closure performance.
• Microbiological assays: Bioburden analysis.

8. Sample Size for the Training Set

The document does not explicitly describe a separate "training set" in the context of machine learning or AI algorithms, as this is not an AI-based device. Instead, the studies detail the performance validation of the system. The various studies use different cohorts of human donors for the collection of blood samples to assess different aspects of the device's performance (e.g., 5 donors for K2EDTA comparator, 48 donors for PAXgene in initial RT-PCR assay validation, 14 and 30 donors for system precision/reproducibility, 10 donors for purity/DNA contamination, 10 donors for each in situ stability condition).

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

As mentioned above, there is no "training set" in the AI sense for this device. The establishment of "ground truth" for the various performance metrics (RNA yield, purity, integrity, etc.) is through well-established and standardized laboratory analytical methods as described in point 7. These methods themselves are considered the "gold standard" for measuring these specific biochemical and molecular parameters.

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