(90 days)
Not Found
Yes
The device description explicitly states that the probesets were selected using "machine learning methods" and that the algorithm was developed using a "machine learning approach".
No
Explanation: This device is an in vitro diagnostic test designed to determine the tissue of origin for tumors by analyzing RNA expression patterns. It is used for diagnostic purposes and does not provide any therapeutic intervention.
Yes
The "Pathwork® Tissue of Origin Test" is explicitly described as an "in vitro diagnostic intended to measure the degree of similarity between the RNA expression patterns in a patient's formalin-fixed, paraffin-embedded (FFPE) tumor and the RNA expression patterns in a database of fifteen tumor types". This directly indicates its use for diagnostic purposes.
No
The device description explicitly states that the Pathwork® Tissue of Origin Test Kit-FFPE is a test kit consisting of the Pathchip microarray, reagents, software, and labeling. The Pathchip microarray is a physical hardware component.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use: The "Intended Use / Indications for Use" section explicitly states that the Pathwork® Tissue of Origin Test is an "in vitro diagnostic intended to measure the degree of similarity between the RNA expression patterns in a patient's formalin-fixed, paraffin-embedded (FFPE) tumor and the RNA expression patterns in a database of fifteen tumor types". This clearly indicates that the device is used to perform tests on biological samples (tumor tissue) outside of the body to provide diagnostic information.
- Device Description: The description details a "test kit consisting of the Pathchip microarray, reagents, software, and labeling". This is consistent with the components of an in vitro diagnostic test.
- Performance Studies: The document includes a "Summary of Performance Studies" which describes a study comparing results obtained with different amounts of RNA, a common type of validation for an IVD.
- Key Metrics: The inclusion of "Key Metrics" like "Concordance" further supports its classification as an IVD, as these metrics are used to evaluate the performance of diagnostic tests.
- Predicate Device: The mention of a "Predicate Device(s)" with a K number (K092967) indicates that this device is being compared to a previously cleared device, which is a process used for regulatory clearance of IVDs.
All of these elements strongly point to the Pathwork® Tissue of Origin Test being an In Vitro Diagnostic device.
No
The letter does not state that the FDA has reviewed and approved or cleared a PCCP for this specific device. The input explicitly states "Control Plan Authorized (PCCP) and relevant text: Not Found".
Intended Use / Indications for Use
The Pathwork® Tissue of Origin Test is an in vitro diagnostic intended to measure the degree of similarity between the RNA expression patterns in a patient's formalin-fixed, paraffin-embedded (FFPE) tumor and the RNA expression patterns in a database of fifteen tumor types (poorly differentiated, undifferentiated and metastatic cases) that were diagnosed according to then current clinical and pathological practice. This test should be evaluated by a qualified physician in the context of the patient's clinical history and other diagnostic test results.
Limitations: The Pathwork Tissue of Origin Test is not intended to establish the origin of tumors (e.g. cancer of unknown primary) that cannot be diagnosed according to current clinical and pathological practice. It is not intended to subclassify or modify the classification of tumors that can be diagnosed by current clinical and pathological practice, nor to predict disease course or survival or treatment efficacy, nor to distinguish primary from metastatic tumor. Tumor types not in the Pathwork Tissue of Origin Test database may have RNA expression patterns that are similar to patterns in the database; therefore, results cannot be used to distinguish tumor types in the database from tumor types not in the database.
Product codes (comma separated list FDA assigned to the subject device)
OIW
Device Description
The Pathwork® Tissue of Origin Test Kit-FFPE is a test kit consisting of the Pathchip microarray, reagents, software, and labeling.
The Pathchip is a custom-designed microarray manufactured by Affymetrix, Inc. (Santa Clara, CA) per Pathwork design requirements and functions in a manner similar to GeneChip HG-U133A. The Pathchip has over 500,000 unique oligonucleotide features (18-micron in size), covering over 18,400 transcript variants (across 22,300 probesets) which in turn represent 14,500 of the best characterized human genes. Each transcript is represented by a probeset, comprised of 11-16 pairs of oligonucleotide probes. The probesets are spatially distributed over the arrav and are used to measure the level of transcription of each sequence represented on the array. For each array, there are 2000 probesets representing 2000 human genes which are used by the Tissue of Origin Test Kit - FFPE algorithm as markers to identify the tissue of origin of the specimen being tested. These probesets were selected using machine learning methods and each set has between 11 and 16 probe pairs of 25 bases whose sequences are matched to mRNA species that are found in human tissue. In addition, the array has 29 probesets that are used for normalization and data verification.
The algorithm of the Pathwork® Tissue of Origin Test was developed using a database of 2196 specimens, divided into independent training and test datasets. The test development used a machine learning approach based on marker selection to build a predictive model. The model consists of a list of markers, a set of reference (support) samples and a set of coefficients. These components are combined to produce 15 Similarity Scores, one for each of the possible tissues on the test panel. Each similarity score ranges from 0 to 100, with a higher score being associated with a higher likelihood that the input specimen has a molecular signature of the corresponding tissue of origin. The 15 similarity scores are scaled to sum up to 100. Each is based on the microarray standardized expression (SE) values of selected biomarkers. The process consists of the following steps:
- Read SE values for the biomarkers used in the Tissue of Origin Test from 1. the input file.
- Compute a decision function ("score") for each of 105 possible pairings of 2. the 15 tissues on the test panel with respect to the sample described by the input SE values.
- Convert the 105 pairwise scores into pairwise probabilities. 3.
- Reduce the 105 pairwise probabilities to 15 Similarity Scores, one for each 4. Tissue of Origin. These are the final 15 Similarity Scores presented in the Tissue of Origin Test Report.
Components included in the kit
Microarray: Pathchip microarrays, packaged in boxes of 5 or 10.
Gene Expression Reagents: Reagents for specimen processing (extraction, amplification, labeling, hybridization, staining and washing).
Report
Tissue of Origin Test Kit-FFPE Report is produced by the Pathwork System Software (by licensed agreement); The Pathwork® System Software receives data from the scanned Pathchip™ microarray and performs data quality control and analysis. The System Software then generates a Pathwork® Tissue of Origin Test Kit-FFPE Report which provides a Similarity Score for each of the 15 tissues on the test panel. The test report is accessible for clinical interpretation via a secure password protected website.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
The probesets were selected using machine learning methods and each set has between 11 and 16 probe pairs of 25 bases whose sequences are matched to mRNA species that are found in human tissue.
The test development used a machine learning approach based on marker selection to build a predictive model.
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
Not Found
Intended User / Care Setting
qualified physician
Description of the training set, sample size, data source, and annotation protocol
The algorithm of the Pathwork® Tissue of Origin Test was developed using a database of 2196 specimens, divided into independent training and test datasets.
Description of the test set, sample size, data source, and annotation protocol
The algorithm of the Pathwork® Tissue of Origin Test was developed using a database of 2196 specimens, divided into independent training and test datasets.
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
The study was a comparison of the same tumor specimens already analyzed using the 510(k) cleared method, with specimens where the amount of starting tissue was diminished to provide between 30 and 150 nanograms of RNA. In addition, the procedure had been modified to include the use of ethanol in the purification of biotinylated DNA, and this modification was also included in the study. Specimens were selected from reserves of FFPE tumor specimens employed for assessment of performance during development of the TOO-FFPE Test. These tumors had extant results obtained when ≥150 ng of RNA had been extracted using the 510(k) cleared method, and they all agreed with their available diagnosis. These tumor specimens were manually dissected under a microscope to provide less tissue for extraction, resulting in smaller amounts of extracted RNA. Several very small specimens were taken from each tumor sample. RNA was extracted from each of the smaller specimens, and the amount of RNA present determined spectroscopically. If a single specimen provided between 30 and 150 ng, and could be concentrated to at least 9.5 ng/ul, it was used. Otherwise, up to 4 extractions were combined until at least 30 ng RNA was present at a concentration of at least 9.5 ng/ul. The final tissues used were at least 0.05 mm3 with at least 60% tumor content. These total RNA samples were carried through the modified assay and results compared to those obtained with the larger amounts of total RNA for the same tissue. - Forty-five turnors, 3 of each of the tumor types in the database, were entered into the study. Comparisons between ≥150 ng RNA speciments processed without ethanol, and 30-150 ng of RNA extracted and processed with ethanol could be made for 43 tumors. Forty-two of these were concordant and one was not, for a % concordance of 97.7% (95% confidence interval of 87.7%, 99.9%). The change was considered validated, because all preestablished criteria were met or exceeded.
Concordance Table:
Comparison: ≥ 150 ng and ethanol absent Versus 30 to 150 ng and ethanol present
Specimens: 43
Concordance Ratio: 42/43
Concordance Percent: 97.7%
Concordance 95% Confidence Interval: [87.7, 99.9]
Discordance Ratio: 1/43
Discordance Percent: 2.3%
Discordance 95% Confidence Interval: [0.1, 12.3]
Similarity score regression plots were obtained comparing the similarity scores for all 15 tissues, for matched pairs of specimens that yielded either ≥150 ng of total RNA processed in the absence of ethanol (x-axis) vs. between 30 and 150 ng of total RNA processed in the presence of ethanol (y-axis). Similarity scores range between 0 and 100. The resulting regression analysis gave an intercept of 0.61 (0.11, 1.10) and a slope of 0.91 (0.88. 0.93) and an R of 0.94.
Bland Altman plot: Made comparing the difference between the highest similarity scores for the ≥150 ng RNA runs and the highest similarity score for the 30-150 ng runs to the average for these two similarity scores. The mean value of the difference was 4 and no trends were observed.
Conclusion: the procedure changes have not changed the performance of the Test.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
% concordance of 97.7% (95% confidence interval of 87.7%, 99.9%).
Regression analysis: intercept of 0.61 (0.11, 1.10) and a slope of 0.91 (0.88. 0.93) and an R of 0.94.
Predicate Device(s)
Reference Device(s)
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information
Not Found
§ 862.3100 Amphetamine test system.
(a)
Identification. An amphetamine test system is a device intended to measure amphetamine, a central nervous system stimulating drug, in plasma and urine. Measurements obtained by this device are used in the diagnosis and treatment of amphetamine use or overdose and in monitoring levels of amphetamine to ensure appropriate therapy.(b)
Classification. Class II (special controls). An amphetamine test system is not exempt if it is intended for any use other than employment or insurance testing or is intended for Federal drug testing programs. The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 862.9, provided the test system is intended for employment and insurance testing and includes a statement in the labeling that the device is intended solely for use in employment and insurance testing, and does not include devices intended for Federal drug testing programs (e.g., programs run by the Substance Abuse and Mental Health Services Administration (SAMHSA), the Department of Transportation (DOT), and the U.S. military).
0
May 16, 2012
.
Pathwork Diagnostics, Inc. 510(k): Device Modification: Tissue of Origin Test Kit-FFPE
SECTION 6 510(k) SUMMARY
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
The assigned 510(k) number is K120489
| 807.92 (a)(1): | Name: | Pathwork® Diagnostics, Inc. |
|---|---|---|
| Address: | 595 Penobscot Drive | |
| Redwood City, CA 94063 |
| Phone: | 650-366-1003 x101 |
|---|---|
| Contact: | Deborah Neff President & CEO |
807.92 (a)(2): Device Name - trade name and common name, and classification
| Trade name: | Pathwork® Tissue of Origin Test Kit-FFPE |
|---|---|
| Common name: | Microarray, reagents and software system kit for gene |
| expression-based diagnostics | |
| Classification: | 21 CFR § 862.3100, Amphetamine Test System |
| Class II | |
| Product Code: | OIW, Software, similarity score algorithm, tissue of origin for |
| malignant tumor types | |
| Panel: | Toxicology (91) |
807.92 (a)(3): Identification of the legally marketed predicate device
The Tissue of Origin Test Kit-FFPE as modified is substantially equivalent to the Pathwork Tissue of Origin Test Kit FFPE cleared under premarket notification K092967 on June 9, 2010.
1
807.92 (a)(4): Device Description
The Pathwork® Tissue of Origin Test Kit-FFPE is a test kit consisting of the Pathchip microarray, reagents, software, and labeling.
The Pathchip is a custom-designed microarray manufactured by Affymetrix, Inc. (Santa Clara, CA) per Pathwork design requirements and functions in a manner similar to GeneChip HG-U133A. The Pathchip has over 500,000 unique oligonucleotide features (18-micron in size), covering over 18,400 transcript variants (across 22.300 probesets) which in turn represent 14,500 of the best characterized human genes. Each transcript is represented by a probeset, comprised of 11-16 pairs of oligonucleotide probes. The probesets are spatially distributed over the arrav and are used to measure the level of transcription of each sequence represented on the array. For each array, there are 2000 probesets representing 2000 human genes which are used by the Tissue of Origin Test Kit - FFPE algorithm as markers to identify the tissue of origin of the specimen being tested. These probesets were selected using machine learning methods and each set has between 11 and 16 probe pairs of 25 bases whose sequences are matched to mRNA species that are found in human tissue. In addition, the array has 29 probesets that are used for normalization and data verification.
The algorithm of the Pathwork® Tissue of Origin Test was developed using a database of 2196 specimens, divided into independent training and test datasets. The test development used a machine learning approach based on marker selection to build a predictive model. The model consists of a list of markers, a set of reference (support) samples and a set of coefficients. These components are combined to produce 15 Similarity Scores, one for each of the possible tissues on the test panel. Each similarity score ranges from 0 to 100, with a higher score being associated with a higher likelihood that the input specimen has a molecular signature of the corresponding tissue of origin. The 15 similarity scores are scaled to sum up to 100. Each is based on the microarray standardized expression (SE) values of selected biomarkers. The process consists of the following steps:
- Read SE values for the biomarkers used in the Tissue of Origin Test from 1. the input file.
- Compute a decision function ("score") for each of 105 possible pairings of 2. the 15 tissues on the test panel with respect to the sample described by the input SE values.
- Convert the 105 pairwise scores into pairwise probabilities. 3.
- Reduce the 105 pairwise probabilities to 15 Similarity Scores, one for each 4. Tissue of Origin. These are the final 15 Similarity Scores presented in the Tissue of Origin Test Report.
2
The Pathwork Specimen Processing Guide contains instructions for the user to process tissue specimens in the manner specimens were processed during the clinical validation of the Pathwork Tissue of Origin Test Kit - FFPE.
Components included in the kit
Microarray: Pathchip microarrays, packaged in boxes of 5 or 10.
Gene Expression Reagents: Reagents for specimen processing (extraction, amplification, labeling, hybridization, staining and washing).
Report
Tissue of Origin Test Kit-FFPE Report is produced by the Pathwork System Software (by licensed agreement); The Pathwork® System Software receives data from the scanned Pathchip™ microarray and performs data quality control and analysis. The System Software then generates a Pathwork® Tissue of Origin Test Kit-FFPE Report which provides a Similarity Score for each of the 15 tissues on the test panel. The test report is accessible for clinical interpretation via a secure password protected website.
807.92 (a)(5): Intended Use
Intended use: The Pathwork® Tissue of Origin Test is an in vitro diagnostic intended to measure the degree of similarity between the RNA expression patterns in a patient's formalin-fixed, paraffin-embedded (FFPE) tumor and the RNA expression patterns in a database of fifteen tumor types (poorly differentiated, undifferentiated and metastatic cases) that were diagnosed according to then current clinical and pathological practice. This test should be evaluated by a qualified physician in the context of the patient's clinical history and other diagnostic test results.
Limitations: The Pathwork Tissue of Origin Test is not intended to establish the origin of tumors (e.g. cancer of unknown primary) that cannot be diagnosed according to current clinical and pathological practice. It is not intended to subclassify or modify the classification of tumors that can be diagnosed by current clinical and pathological practice, nor to predict disease course or survival or treatment efficacy, nor to distinguish primary from metastatic tumor. Tumor types not in the Pathwork Tissue of Origin Test database may have RNA expression patterns that are similar to patterns in the database; therefore, results cannot be used to distinguish tumor types in the database from tumor types not in the database.
807.92 (a)(6): Technological Similarities and Differences to Predicate
Pathwork Diagnostics, Inc.
3
| Comparison with Unmodified Device | ||
|---|---|---|
| Feature/ | ||
| component | Tissue of Origin Test Kit-FFPE | |
| K092967 | Modified Tissue of Origin Test Kit-FFPE | |
| Intended use | The Pathwork Tissue of Origin Test | |
| is an in vitro diagnostic intended to | ||
| measure the degree of similarity | ||
| between the RNA expression | ||
| patterns in a patient's formalin fixed, | ||
| paraffin embedded (FFPE) tumor | ||
| and the RNA expression patterns in | ||
| a database of fifteen tumor types | ||
| (poorly differentiated, | ||
| undifferentiated, and metastatic | ||
| cases) that were diagnosed | ||
| according to then current clinical | ||
| and pathological practice. This test | ||
| should be evaluated by a qualified | ||
| physician in the context of the | ||
| patient's clinical history and other | ||
| diagnostic test results. | Same. | |
| Same chip, same location of all gene | ||
| expression probes. | ||
| Microarray | ||
| Equipment | Pathchip® | |
| Hybridization oven | Same | |
| Stain, wash | Same | |
| Scanner | Same or substantially equivalent | |
| Purification of | ||
| biotinylated | ||
| cDNA | As Described in the Labeling in | |
| K092976 | Changed, to add ETOH | |
| Changed to: Allow a minimum of | ||
| 30ng total RNA extracted from tissue | ||
| specimen is required at a | ||
| concentration of 10 ng/µl (± 0.5 | ||
| ng/µl). If the specimen has an area |