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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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MammaPrint® is a gualitative in vitro diagnostic test service, performed in a single laboratory, using the gene expression profile of fresh breast cancer tissue samples to assess a patients' risk for distant metastasis (up to 10 years for patients less than 61 years old, up to 5 years for patients ≥ 61 years).

The test is performed for breast cancer patients with Stage I or Stage II disease, with a tumor size of ≤ 5.0 cm and lymph node negative. The MammaPrint result is indicated for use by physicians as a prognostic marker only, along with other clinicopathological factors.

The MammaPrint service is a microarray based gene expression analysis of a tumor. The analysis is based on several processes: isolation of RNA from frozen tumor tissue sections, DNA'se treatment of isolated RNA, linear amplification and labeling of DNA'se treated RNA, cRNA purification, hybridization of the cRNA to the MammaPrint microarray, scanning the MammaPrint microarray and data acquisition (feature extraction), index calculation and determination of the risk of distant recurrence in breast cancer patients.

The MammaPrint analysis is designed to determine the gene activity of specific genes in a tissue sample compared to a reference standard. The result is an expression profile, or fingerprint, of the sample.

The correlation of the sample expression profile to a template (the mean expression profile of 44 tumors with a known good clinical outcome) is calculated and the molecular profile index of the sample is determined (Low Risk, High Risk).

Here's a breakdown of the acceptance criteria and the study information for the MammaPrint® device, based on the provided text:

MammaPrint® Acceptance Criteria and Study Information

1. Acceptance Criteria and Reported Device Performance

The provided document primarily focuses on analytical performance as internally validated and clinical performance as demonstrated through peer-reviewed studies. It doesn't explicitly state "acceptance criteria" in a typical pass/fail numerical sense for clinical performance, but rather presents the performance achieved by the device in various clinical settings.

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

The document describes several clinical studies, which served as the basis for clinical performance validation. These studies effectively act as the "test set" for demonstrating clinical utility.

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

The MammaPrint test determines a "risk of distant recurrence." The "ground truth" in these studies is the actual clinical outcome, specifically distant metastasis-free survival. This type of ground truth is established through long-term follow-up of patients, typically overseen by clinical oncologists and other medical professionals, rather than a panel of experts reviewing images or other diagnostic outputs to establish a consensus. The studies are retrospective analyses of patient cohorts with known clinical outcomes.

Therefore, the concept of "number of experts used to establish ground truth" with specific qualifications in the traditional sense (e.g., radiologists for imaging) does not directly apply here. The "ground truth" is the observed patient outcome over time, documented by treating physicians and medical records.

4. Adjudication Method for the Test Set

Given that the ground truth is patient outcomes (distant metastasis-free survival) over many years, an adjudication method for a "test set" like 2+1 or 3+1 typically used for medical image review is not applicable. Clinical outcomes are factual events recorded over time.

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

No Multi-Reader Multi-Case (MRMC) comparative effectiveness study is mentioned in the provided text. MammaPrint is a gene expression profiling test, not an imaging device or a tool directly interpreted by human readers in the same way an MRI or X-ray would be. Its output is a risk classification (Low Risk, High Risk), which is directly provided to the physician for consideration alongside other clinical factors. The improvement in human reader performance with AI assistance is not a relevant metric for this type of device.

6. Standalone (Algorithm Only) Performance

Yes, the studies presented demonstrate the standalone performance of the MammaPrint algorithm. The clinical studies (Nature, NEJM, Transbig, Older Age NKI/AVL) evaluate the prognostic power of the MammaPrint profile (generated by the algorithm) in predicting distant metastasis-free survival. The reported metastasis-free survival rates for "low risk profile" and "high risk profile" directly reflect the algorithm's ability to stratify patients based solely on its gene expression analysis.

7. Type of Ground Truth Used

The type of ground truth used for the clinical studies is patient outcomes data, specifically distant metastasis-free survival. This is a robust and objective measure of a patient's disease progression.

8. Sample Size for the Training Set

The document states that the Nature Paper (1) describes the "Development of breast cancer prognosis 70-gene profile (LNO, <55)" using 78 patients. This study likely represents the initial cohort used to develop or train the 70-gene signature that underlies MammaPrint. While not explicitly called a "training set" in the modern machine learning sense, this cohort was instrumental in defining the profile.

The MammaPrint algorithm itself correlates a sample's expression profile to a template (the mean expression profile of 44 tumors with a known good clinical outcome). These 44 tumors could be considered part of the "training" or reference data for the algorithm's core functionality.

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

For the "Nature Paper" (which describes the development of the 70-gene profile):

• The ground truth would have been established through long-term clinical follow-up and patient outcomes data, similar to the test sets. Patients in this development cohort would have had their distant metastasis status recorded over a period of years (e.g., 5-year metastasis risk).
• For the 44 tumors used to create the "template" for the MammaPrint Index calculation, their "known good clinical outcome" would have been established based on observed excellent patient prognosis/long-term metastasis-free survival from clinical records.

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