(90 days)
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.
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.
Here's an analysis of the acceptance criteria and the study proving the device meets them, based on the provided text:
Acceptance Criteria and Device Performance
| Acceptance Criteria | Reported Device Performance |
|---|---|
| Percent agreement between the modified method (30-150ng RNA with ethanol) and the original method (≥150ng RNA without ethanol) | 97.7% (95% CI: 87.7%, 99.9%) |
Study Details
-
Sample Size and Data Provenance:
- Test Set Sample Size: 43 tumor specimens were actually analyzed for comparison. The study aimed for 45 tumors (3 of each of the 15 tumor types).
- Data Provenance: The specimens were "reserves of FFPE tumor specimens employed for assessment of performance during development of the TOO-FFPE Test." These pre-existing specimens had prior results obtained using the 510(k) cleared method. The text does not specify the country of origin, but the company is based in Redwood City, CA, USA. The data is retrospective, as it used pre-existing specimens with "extant results."
-
Number of Experts and Qualifications for Ground Truth:
- The primary ground truth for this modification study was the result obtained from the original 510(k) cleared method using ≥150 ng of RNA without ethanol. The text states these original results "all agreed with their available diagnosis."
- The ground truth for the original validation of the device (K092967) was established by "then current clinical and pathological practice." The text does not specify the number or qualifications of experts involved in establishing these diagnoses for the original specimens.
-
Adjudication Method for Test Set: Not applicable. The study was a comparison of results from two different processing methods on the same specimens against a pre-established "available diagnosis." There wasn't an expert adjudication process described for new interpretations in this specific modification study.
-
Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study: No. This study focused on the technical performance equivalence of a modified RNA extraction and purification protocol, not on human reader performance with or without AI assistance.
-
Standalone Performance (Algorithm Only without Human-in-the-loop): Yes, the study evaluated the performance of the algorithm with different input RNA quantities and processing steps. The output (Similarity Scores) is generated by the algorithm and then compared. While the ultimate intended use involves a physician's interpretation, this particular study focused on the analytical performance of the modified test.
-
Type of Ground Truth Used:
- For the modification study, the ground truth was the result obtained from the original 510(k) cleared method for the same specimen, which "agreed with their available diagnosis."
- For the original establishment of the device's accuracy (referenced as the predicate device), the ground truth was established by "available diagnosis" or "current clinical and pathological practice."
-
Sample Size for Training Set: The algorithm for the Pathwork® Tissue of Origin Test was developed using a database of 2196 specimens, divided into independent training and test datasets. The exact split between training and test sets from this 2196 is not provided, but the sample size for the overall algorithm development is stated.
-
How Ground Truth for Training Set was Established: The ground truth for the training set (part of the 2196 specimens) was established based on diagnoses "according to then current clinical and pathological practice."
§ 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).