(246 days)
Not Found
No
The device uses a defined algorithm based on gene expression profiles and clinical variables, not a system that learns or adapts from data. The algorithm is based on pre-defined "prototypical expression profiles (centroids)" and fixed calculations, not machine learning.
No.
The device is an in vitro diagnostic assay used to assess a patient's risk of distant recurrence of breast cancer, not to provide therapy.
Yes
The document explicitly states that "The Prosigna™ Breast Cancer Prognostic Gene Signature Assay is an in vitro diagnostic assay". While it also states "Prosigna is not intended for diagnosis, to predict or detect response to therapy, or to help select the optimal therapy for patients", this exclusion refers to making a new diagnosis of breast cancer or selecting treatment, not its role as a diagnostic tool for prognosis. The assay functions as a prognostic indicator for distant recurrence-free survival, which is a diagnostic function to assess a patient's risk.
No
The device is an in vitro diagnostic assay that requires specific hardware components (NanoString nCounter® Dx Analysis System, Prep Station, Digital Analyzer) and reagents to process biological samples and generate data, in addition to the software algorithm.
Yes, this device is an IVD (In Vitro Diagnostic).
The text explicitly states in the "Intended Use / Indications for Use" section: "The Prosigna™ Breast Cancer Prognostic Gene Signature Assay is an in vitro diagnostic assay..."
Furthermore, the description details that the assay is performed on FFPE breast tumor tissue, which is a biological sample taken from the body, and it analyzes gene expression data to provide information about a patient's risk of distant recurrence. This aligns with the definition of an in vitro diagnostic device, which is used to examine specimens derived from the human body to provide information for diagnosis, monitoring, or treatment.
N/A
Intended Use / Indications for Use
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:
-
A prognostic indicator for distant recurrence-free survival at 10 years in post-menopausal 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.
-
A prognostic indicator for distant recurrence-free survival at 10 years in post-menopausal 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.
Special Conditions for Use: Prosigna™ is not intended for diagnosis, to predict or detect response to therapy, or to help select the optimal therapy for patients.
Product codes
NYI, NSU
Device Description
Used together, the Prosigna™ Breast Cancer Prognostic Gene Signature Assay and nCounter Dx Analysis System are a nucleic acid hybridization and image analysis system based upon coded probes designed to detect the messenger RNA transcribed from 58 genes. The test input is purified RNA from FFPE breast tumor specimens which are acquired from surgical resection. The Prosigna assay uses gene-specific probe pairs that hybridize directly to the mRNA transcripts in solution. The nCounter Dx Analysis System delivers direct, multiplexed measurements of gene expression through digital readouts of the relative abundance of the mRNA transcripts. Specifications are included as part of the Prosigna Assay to control for sample quality, RNA quality, and process quality. Prosigna simultaneously measures the expression levels of 50 genes used in the PAM50 classification algorithm (Parker et al., 2009), 8 housekeeping genes used for signal normalization, 6 positive controls, and 8 negative controls in a single hybridization reaction, using nucleic acid probes designed specifically to those genes. The Prosigna assay utilizes prototypical expression profiles (centroids) which are associated with and define each of the four PAM50 molecular subtypes of breast cancer. The software algorithm produces a Prosigna Score (referred to as ROR Score or Risk of Recurrence Score in the literature (Dowsett et al., 2013)) based on the similarity of the expression profile to each PAM50 molecular subtype, as well as the gross pathological tumor size and a proliferation score computed from a subset of genes. Three risk categories (low, intermediate and high) were defined based on a study with over 1007 patient samples associating Prosigna score with longterm outcome.
The required components for the Prosigna 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 test output is a patient specific report which includes a Prosigna score (0-100) and risk category (low/intermediate/high).
Mentions image processing
Yes
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
breast tumor tissue
Indicated Patient Age Range
post-menopausal women
Intended User / Care Setting
Prescription Use
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
For the ABCSG-8 study, all samples were sent to, and all tests were performed at, an independent academic pathology laboratory. Of the 1,620 tissues available for testing in the ABCSG-8 study, 25 (1.5%) did not pass pre-defined pathology review criteria for adequate tumor, 73 of the 1595 tissue samples (4.6%) with viable invasive tissue did not pass pre-defined QC specifications for quantity and quality of extracted RNA, and 44 of the 1522 RNA samples (2.9%) failed the Prosigna assay QC specifications leaving a total of 1,478 (91.2%) available for analysis. Of the 1,478 patients available for analysis, 155 had distant recurrences and 194 had local or distant recurrence or death due to breast cancer. The median follow-up for the trial was 10 years.
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Analytical Performance:
A number of pre-analytical and analytical studies were carried out with the Prosigna Assay to assess the precision, reproducibility, cutoff, sensitivity, specificity and robustness of the assay. Analytical studies also addressed specimen shipping and storage, reagent stability, RNA extraction specifications, tissue requirements, RNA input, cross-hybridization, crosscontamination and tissue interferents testing.
Technical validity was demonstrated in two multi-site (3 sites total), blinded and randomized studies which were designed to test variability across operators, sites, instruments, reagent lots, time, runs and sample position within a 10-sample cartridge. One study assessed reproducibility including pre-analytical factors with a total of 43 tissue samples (FFPE) and the other assessed assay precision with 5 pooled RNA samples. All reproducibility samples were within the intended use patient population indicated by Prosigna, and constituted a large range of Prosigna scores (across 94 Prosigna Score units).
The standard deviation (SD) of the Prosigna Score from the 5 pooled RNA samples was
§ 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.
0
Image /page/0/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo features a stylized representation of a human figure, composed of three overlapping profiles facing to the right. The profiles are rendered in black and white. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged around the logo.
Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
July 12, 2016
Nanostring Technologies Sylva Krizan, Ph.D. Regulatory Affairs Specialist 530 Fairview Ave N, Suite 2000 Seattle, WA 98109
Re: K130010
Trade/Device Name: ProsignaTM Breast Cancer Prognostic Gene Signature Assay Regulation Number: 21 CFR §866.6040 Regulation Name: Gene expression profiling test system for breast cancer prognosis Regulatory Class: Class II Product Code: NYI, NSU Dated: August 9, 2013 Received: August 9, 2013
Dear Dr. Krizan:
This letter corrects our substantially equivalent letter of September 6, 2013.
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration. Iisting of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of
1
medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
If you desire specific advice for your device on our labeling regulation (21 CFR Part Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled. "Misbranding by reference to premarket notification" (21CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to
http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.
Sincerely.
Reena Philip -S
Reena Philip, Ph.D. Director Division of Molecular Genetics and Pathology Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
2
510(k) Number (if known): K130010
Device Name: Prosigna™ Breast Cancer Prognostic Gene Signature Assay
Indications for Use:
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:
A prognostic indicator for distant recurrence-free survival at 10 years in post-menopausal 1. 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.
- A prognostic indicator for distant recurrence-free survival at 10 years in post-menopausal 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.
Special Conditions for Use: Prosigna is not intended for diagnosis, to predict or detect response to therapy, or to help select the optimal therapy for patients.
Prescription Use x (Part 21 CFR 801 Subpart D)
Over-The-Counter Use _ (21 CFR 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostics and Radiological Health (OIR)
/un fo Au -S
Division Sign-Off Office of In Vitro Diagnostics and Radiological Health
510(k) K130010
Page 1 of 1
3
510(k) Summary: K130010
Applicant: NanoString Technologies, Inc.
Establishment Registration Number: 3006389928
Contact person:
Sylva Krizan, Ph.D. Regulatory Affairs Specialist NanoString Technologies 530 Fairview Avenue North, Suite 2000 Seattle, WA 98109
Phone: (206) 432-8854 Fax: (206) 378-6288
Summary Date:
September 6, 2013
Device Name:
Trade name: Prosigna™ Breast Cancer Prognostic Gene Signature Assay Common Name: NanoString gene expression profiling test for breast cancer prognosis
Classification:
21 CFR § 866.6040: Gene expression profiling test system for breast cancer prognosis
Guidance Document:
Class II Special Controls Guidance Document: Gene Expression Profiling Test System for Breast Cancer Prognosis, issued on May 9, 2007
Product Code:
NYI
Indications for Use / Intended Use:
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:
4
- 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.
A prognostic indicator for distant recurrence-free survival at 10 years in post-2. menopausal 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.
Special Conditions for Use:
Prosigna™ is not intended for diagnosis, to predict or detect response to therapy, or to help select the optimal therapy for patients.
Device Description:
Used together, the Prosigna™ Breast Cancer Prognostic Gene Signature Assay and nCounter Dx Analysis System are a nucleic acid hybridization and image analysis system based upon coded probes designed to detect the messenger RNA transcribed from 58 genes. The test input is purified RNA from FFPE breast tumor specimens which are acquired from surgical resection. The Prosigna assay uses gene-specific probe pairs that hybridize directly to the mRNA transcripts in solution. The nCounter Dx Analysis System delivers direct, multiplexed measurements of gene expression through digital readouts of the relative abundance of the mRNA transcripts. Specifications are included as part of the Prosigna Assay to control for sample quality, RNA quality, and process quality. Prosigna simultaneously measures the expression levels of 50 genes used in the PAM50 classification algorithm (Parker et al., 2009), 8 housekeeping genes used for signal normalization, 6 positive controls, and 8 negative controls in a single hybridization reaction, using nucleic acid probes designed specifically to those genes. The Prosigna assay utilizes prototypical expression profiles (centroids) which are associated with and define each of the four PAM50 molecular subtypes of breast cancer. The software algorithm produces a Prosigna Score (referred to as ROR Score or Risk of Recurrence Score in the literature (Dowsett et al., 2013)) based on the similarity of the expression profile to each PAM50 molecular subtype, as well as the gross pathological tumor size and a proliferation score computed from a subset of genes. Three risk categories (low, intermediate and high) were defined based on a study with over 1007 patient samples associating Prosigna score with longterm outcome.
The required components for the Prosigna 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 test output is a patient specific report which includes a Prosigna score (0-100) and risk category (low/intermediate/high).
5
Analytical Performance:
A number of pre-analytical and analytical studies were carried out with the Prosigna Assay to assess the precision, reproducibility, cutoff, sensitivity, specificity and robustness of the assay. Analytical studies also addressed specimen shipping and storage, reagent stability, RNA extraction specifications, tissue requirements, RNA input, cross-hybridization, crosscontamination and tissue interferents testing.
Technical validity was demonstrated in two multi-site (3 sites total), blinded and randomized studies which were designed to test variability across operators, sites, instruments, reagent lots, time, runs and sample position within a 10-sample cartridge. One study assessed reproducibility including pre-analytical factors with a total of 43 tissue samples (FFPE) and the other assessed assay precision with 5 pooled RNA samples. All reproducibility samples were within the intended use patient population indicated by Prosigna, and constituted a large range of Prosigna scores (across 94 Prosigna Score units).
The standard deviation (SD) of the Prosigna Score from the 5 pooled RNA samples was 20% | 61-100 | 41-100 |
The following figures are the Kaplan-Meier curves showing the percent of patients without distant recurrence by risk-group through 10 years for all patients from the ABCSG-8 study, by nodal status.
9
DRFS by Risk Group for Node-Negative Patients
Image /page/9/Figure/1 description: This image is a Kaplan-Meier plot showing the percent without distant recurrence over a 10-year follow-up period for three risk groups: low-risk, intermediate-risk, and high-risk. The y-axis represents the percent without distant recurrence, ranging from 0 to 1, while the x-axis represents the follow-up time in years, ranging from 0 to 10. The low-risk group has the highest percentage without distant recurrence, followed by the intermediate-risk group, and then the high-risk group.
Summary: DRFS by Risk Group for Node-Negative Patients
| Risk Group | Number of Patients (%) | Number of Events Through 10 Years | Estimated Percent Without Recurrence at 10 years [95% CI] |
|---|---|---|---|
| Low | 487 (47%) | 15 | 96.6% [94.4% - 97.9%] |
| Intermediate | 335 (32%) | 28 | 90.4% [86.3% - 93.3%] |
| High | 225 (21%) | 32 | 84.3% [78.4% - 88.6%] |
| Total | 1,047 (100%) | 75 |
10
DRFS by Risk Group for Node-Positive (1-3 nodes) Patients
Summary: DRFS by Risk Group for Node-Positive (1-3 nodes) Patients
| Risk Group | Number of Patients (%) | Number of Events
Through 10 Years | Estimated Percent Without Distant
Recurrence at 10 years [95% CI] |
|------------|------------------------|--------------------------------------|----------------------------------------------------------------------|
| Low | 158 (41%) | 7 | 94.2% [88.1%-97.2%] |
| High | 224 (59%) | 46 | 75.8% [68.9%-81.4%] |
| Total | 382 (100%) | 53 | |
The Prosigna Score was demonstrated to add significant prognostic information over and above the standard clinical and treatment variables both when included as a continuous measure and when included using pre-defined risk groups. The low-risk groups (each of node-negative and node-positive patients) had 10-year DRFS well above 90% and was separated from the high-risk group by more than a 10% probability of recurrence at 10 years. The Prosigna Score (continuous and risk-group based) showed similar prognostic information in various subgroups.
A C-index analysis was used to evaluate the correlation between the Prosigna Score and the time to distant recurrence. The C-index analysis was restricted to comparing patient samples with Prosigna Scores that differed by only 5-10 Prosigna Score units. This analysis showed that there is statistically significant in small changes in Prosigna Score (P