(256 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 (Origin Test Kit-FFPE) is a test kit consisting of the Pathchip microarray, reagents, software, Pathwork Specimen Processing Guide and Guide to Report Interpretation (GRI). The Pathchip is a custom-designed microarray that functions in a manner similar to GeneChip HG-U133A. The Pathchip has over 500,000 unique oligonucleotide features covering over 18,400 transcript variants (across 22,300 probesets) which in turn represent 14,500 of the best characterized human genes. For each array, there are 2000 probesets representing 2000 human genes which are used by the 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. The algorithm of the Origin Test Kit-FFPE 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 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 reading SE values, computing a decision function for pairwise tissue pairings, converting pairwise scores to probabilities, and reducing pairwise probabilities to 15 Similarity Scores. The Pathwork Specimen Processing Guide (SPG) contains instructions for processing tissue specimens. The specimen used is a formalin-fixed, paraffin-embedded (FFPE) specimen containing at least 60% viable tumor. Total RNA is isolated and processed through a two-cycle RNA amplification, hybridization to the Pathchip microarray, washing and scanning, data acquisition, data verification, standardization of signal intensities, determination of similarity to 15 tissues of origin, and generation of a Report. The CEL file from each laboratory is transported to Pathwork Diagnostics for analysis using the Pathwork System Software (PSS). The PSS converts the CEL file to gene expression measurements, performs data verification, normalizes the data, performs statistical tests, and produces a report summarizing the 15 Similarity Scores. The report quantifies the similarity of the RNA expression pattern in a tumor specimen to expression patterns found in tumor specimens from 15 known tissues of origin and is provided back to the laboratory over a secure internet connection in pdf format. Clinical laboratory customers use the report for incorporation into the surgical pathology report delivered to the requesting physician. The report presents the 15 computed Similarity Scores in a graphical format. The ordering physician interprets the report using the Guide to Report Interpretation (GRI).
Acceptance Criteria and Study Details for Pathwork® Tissue of Origin Test Kit-FFPE
1. Table of Acceptance Criteria and Reported Device Performance
| Metric | Acceptance Criteria (Implicit) | Reported Device Performance (Clinical Validation Study) |
|---|---|---|
| Agreement with Available Diagnosis (Overall) | At least 80% agreement | 88.5% (95% CI [85.3, 91.3]) |
| Non-agreement with Available Diagnosis (Overall) | No more than 20% non-agreement | 11.5% (95% CI [8.7, 14.7]) |
| Probability of True Positive Tissue Call (when Similarity Score reported) | Not explicitly stated, but high accuracy expected | 88.5% (95% CI [85.3, 91.3]) |
| Probability of Not Being Tissue of Origin (when Similarity Score ≤ 5) | Not explicitly stated, but high exclusionary accuracy expected | 99.8% (95% CI [99.7, 99.9]) |
| Lab-to-Lab Concordance (Overall) | Not explicitly stated, but high reproducibility expected | 89.3% (133/149 paired comparisons) |
| Lab-to-Lab Concordance (Avg Highest Similarity Score 60-100) | Not explicitly stated, but very high reproducibility expected | 100% |
| Lab-to-Lab Concordance (Avg Highest Similarity Score 20-40) | Not explicitly stated, but high reproducibility expected | 93.1% |
Note: The document explicitly states "Each laboratory was expected to achieve the overall acceptance criteria of at least 80% agreement with the available diagnosis, with no more than 20% non-agreement." This was met by all three labs in the reproducibility study (Table 6.4) and the overall clinical validation (Table 6.5). Other criteria are inferred from the reported performance, implying they met the implicit expectations for a successful validation.
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size: 462 specimens (from an initial 598 tumor specimens processed) met the labeling limitations for tumor grade and available diagnosis and passed data verification quality tests.
- Data Provenance: The document does not explicitly state the country of origin. However, the study involved "three different processing laboratories," implying a multi-site clinical validation. The data is retrospective, as it utilizes existing formalin-fixed, paraffin-embedded (FFPE) tumor specimens with previously established "available diagnoses."
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
- The document refers to "available diagnosis established for each specimen" as the ground truth. It is stated that these diagnoses were made "according to then current clinical and pathological practice."
- Number of Experts: Not specified.
- Qualifications of Experts: Not specified beyond the implication of being experts in "clinical and pathological practice."
4. Adjudication Method for the Test Set
- The document does not describe a formal adjudication method for establishing the ground truth (available diagnosis). It states the device results were "compared to available diagnosis established for each specimen." This suggests that the existing clinical and pathological diagnoses were accepted as the ground truth without further expert review or adjudication for the study.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No, an MRMC comparative effectiveness study was not explicitly described. The study focused on the standalone performance of the device against established diagnoses. While the device is intended for interpretation by a qualified physician, the study does not compare human reader performance with and without AI assistance to determine an effect size.
6. Standalone Performance Study
- Yes, a standalone performance study was done. The entire clinical validation described in Section 807.92 (b)(2) is a standalone study, evaluating the algorithm's performance (Pathwork® Tissue of Origin Test Kit-FFPE) in identifying the tissue of origin by comparing its results directly against the "available diagnosis" for each specimen.
7. Type of Ground Truth Used
- Expert Consensus / Pathology / Outcomes Data: The ground truth used was the "available diagnosis established for each specimen," which was based on "current clinical and pathological practice." This strongly implies a combination of morphological pathology (histopathology) and clinical assessment, likely representing an expert consensus or standard clinical diagnosis process. It is not outcomes data.
8. Sample Size for the Training Set
- The algorithm was developed using a database of 2196 specimens, which was "divided into independent training and test datasets." The exact split between training and the developmental test set (different from the clinical validation test set mentioned above) is not precisely specified for the training set alone, but the 2196 specimens were used for algorithm development.
9. How the Ground Truth for the Training Set Was Established
- The ground truth for the specimens within the 2196-specimen database used for algorithm development was "diagnosed according to then current clinical and pathological practice." This is consistent with the method for the clinical validation test set, implying clinical and pathological diagnoses.
§ 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).