(129 days)
The Prosigna® Breast Cancer Prognostic Gene Signature Assay is an in vitro diagnostic assay which is performed on the NanoString nCounter® Dx Analysis System using FFPE breast tumor tissue previously diagnosed as invasive breast carcinoma. This qualitative assay utilizes gene expression data, weighted together with clinical variables to generate a risk category and numerical score, to assess a patient's risk of distant recurrence of disease.
The Prosigna Breast Cancer Prognostic Gene Signature Assay is indicated in female breast cancer patients who have undergone surgery in conjunction with locoregional treatment consistent with standard of care, either as:
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A prognostic indicator for distant recurrence-free survival at 10 years in postmenopausal women with Hormone Receptor-Positive (HR+), lymph node-negative, Stage I or II breast cancer to be treated with adjuvant endocrine therapy alone, when used in conjunction with other clinicopathological factors.
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A prognostic indicator for distant recurrence-free survival at 10 years in postmenopausal women with Hormone Receptor-Positive (HR+), lymph node-positive (1-3 positive nodes), Stage II breast cancer to be treated with adjuvant endocrine therapy alone, when used in conjunction with other clinicopathological factors. The device is not intended for patients with 4 or more positive nodes
The required components for the Prosigna™ Breast Cancer Prognostic Gene Signature Assay include the RNA Isolation kit (manufactured by Roche), Prosigna reagents (Reference Sample, CodeSet, Prep Pack, Cartridge(s) and Prep Plate) and the instruments that comprise the nCounter Dx Analysis System; the Prep Station and Digital Analyzer.
The assay requires microdissection of tumor from FFPE biopsies, isolation of RNA using a Roche RNA isolation kit, transfer of RNA to PCR tubes for hybridization before placing onto the prep station. Two sets of probes specific to each of 58 RNAs are added to the hybridization reaction. These consist of biotin-labeled magnetic probes to purify the RNAs and capture them on the assay cartridge and fluorescent "barcode" probes to detect and quantify individual RNAs. The patient sample and probes are pipetted automatically into the Prosigna test cartridge by the Prep Station. The prep station uses magnetic bead capture and washing to remove excess RNA and un-hybridized probes. The isolated and hybridized RNA species are then bound via biotin on the capture probe randomly to streptavidin on the cartridge. The fluorescent molecules are then aligned on the cartridge by addition of an electric current. The cartridge is then transferred to the Digital Analyzer where the cartridge is scanned and digital analysis software is used to count the number of each RNA species present. The amount of each RNA is then put into a proprietary algorithm to produce a Prosigna score.
The test output is a patient specific report which includes a Prosigna score (0-100) and risk category (low/intermediate/high).
This document describes the FDA's decision to clear the Prosigna™ Breast Cancer Prognostic Gene Signature Assay (K141771) based on its substantial equivalence to a predicate device (K130010). The submission in question for K141771 relates to a modification of the device configuration and software, specifically introducing a 4-sample kit configuration and updating the instrument software. Therefore, the acceptance criteria and study data presented primarily focus on demonstrating that these modifications do not negatively impact the performance established by the predicate device.
1. Table of Acceptance Criteria and Reported Device Performance
For K141771, the primary acceptance criterion related to device performance was to demonstrate that the new 4-sample kit configuration and updated software produced results substantially equivalent to the previously cleared 10-sample kit configuration.
| Acceptance Criteria | Reported Device Performance (K141771) |
|---|---|
| Equivalence of Prosigna Scores between 4-sample and 10-sample kit configurations | Deming Regression: Data was linear over the range of the assay with no outliers between the two methods, indicating substantial equivalence. No value deviated by more than 2 units from the average score when run using either configuration. |
| Bland-Altman Analysis: Variations in data using the 4-kit versus the 10-kit configuration did not bias results. | |
| No change in risk categorization (Low/Intermediate/High) between 4-sample and 10-sample kit configurations | No changes in risk categorization occurred between the 4-kit and 10-kit configurations. |
Note: The document explicitly states "See Predicate Device K130010 for Analytical Performance Data" and "See Predicate Device K130010 for Clinical Performance Data." This means that the core analytical and clinical performance acceptance criteria and their supporting studies were primarily established during the clearance of the predicate device (K130010). The K141771 submission focused on demonstrating that changes to the device (new kit configuration, software) did not degrade this established performance.
2. Sample Size Used for the Test Set and Data Provenance
For the specific comparison study outlined in K141771 (comparing the 4-sample and 10-sample kits):
- Sample Size: Forty (40) samples of RNA previously extracted from FFPE breast tissue were tested with both configurations.
- Data Provenance: The document does not specify the country of origin of the data. It indicates the samples were "previously extracted from FFPE breast tissue," implying the data was retrospective in nature for this specific comparison.
For the original clinical performance data (referenced as part of K130010):
- Sample Size: "a study with over 1007 patient samples associating Prosigna score with long-term outcome, defined by distance recurrence free survival at 10 years (DRFS) (Table 2)."
- Data Provenance: Not specified in this document for the 1007 patient sample study, but it would have been part of the K130010 submission.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
This information is not directly applicable to the K141771 submission's comparison study, as the ground truth was the Prosigna score itself, as generated by the instrument. The study compared the scores generated by two different configurations of the same device.
For the original clinical validation (referenced from K130010), the ground truth for "distant recurrence-free survival at 10 years (DRFS)" would typically be established based on patient follow-up data, which is objective outcomes data rather than subjective expert consensus.
4. Adjudication Method for the Test Set
Not applicable to the K141771 comparison study as there was no expert review or human adjudication involved in generating the Prosigna scores. The comparison was between two automated outputs of the device.
5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was done
No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. The device (Prosigna Assay) is an in vitro diagnostic (IVD) test that provides an automated, objective score. It is not an imaging AI diagnostic system designed to assist human readers.
6. If a Standalone (i.e. algorithm only without human-in-the loop performance) was done
The Prosigna Assay is inherently a standalone algorithm. It takes gene expression data and clinical variables as input and produces a risk category and numerical score as output without human intervention in the scoring process. The performance of this standalone algorithm was presumably established and validated in the clinical studies for the predicate device (K130010), which involved "a study with over 1007 patient samples associating Prosigna score with long-term outcome, defined by distance recurrence free survival at 10 years (DRFS)."
7. The Type of Ground Truth Used
The ground truth for the clinical validation of the Prosigna Assay (for K130010) was outcomes data, specifically "distant recurrence free survival at 10 years (DRFS)". This is a definitive clinical outcome, not expert consensus or pathology review of the assay results themselves.
8. The Sample Size for the Training Set
The document does not specify the sample size for the training set. It mentions "Three risk categories (low, intermediate and high) were defined based on a study with over 1007 patient samples associating Prosigna score with long-term outcome...". This "study" likely encompassed both the development/training and validation of the algorithm, but the specific breakdown is not provided here.
9. How the Ground Truth for the Training Set was Established
The ground truth for the training set (or the 1007 patient study mentioned) was established based on long-term clinical outcomes, specifically "distance recurrence free survival at 10 years (DRFS)". This means that for each patient in the dataset, their disease recurrence status was tracked for 10 years after initial treatment.
§ 866.6040 Gene expression profiling test system for breast cancer prognosis.
(a)
Identification. A gene expression profiling test system for breast cancer prognosis is a device that measures the ribonucleic acid (RNA) expression level of multiple genes and combines this information to yield a signature (pattern or classifier or index) to aid in prognosis of previously diagnosed breast cancer.(b)
Classification. Class II (special controls). The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: Gene Expression Profiling Test System for Breast Cancer Prognosis.” See § 866.1(e) for the availability of this guidance document.