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The PGDx elio™ tissue complete assay is a qualitative in vitro diagnostic device that uses targeted next generation sequencing of DNA isolated from formalin-fixed, paraffin-embedded tumor tissue from patients with solid malignant neoplasms to detect tumor gene alterations in a broad multi-gene panel.

PGDx elio tissue complete is intended to provide tumor mutation profiling information on somatic alterations (SNVs, small insertions and deletions, one amplification and four translocations), microsatellite instability (MSI) and tumor mutation burden (TMB) for use by qualified healthcare professionals in accordance with professional guidelines in oncology for previously diagnosed cancer patients, and is not conclusive or prescriptive for labeled use of any specific therapeutic product.

PGDx elio tissue complete is an in vitro diagnostic assay that uses NGS to detect turnor gene alterations in genomic DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumor tissue from a variety of tumor types, using a targeted panel (505 genes). The assay takes less than 7 days from DNA to report and provides information on single nucleotide variants (SNVs) in a range of GC content and genomic contexts, insertion/ deletions (indels), 1 amplification as well as 4 translocations. It also identifies microsatellite instability based on select mononucleotide tracts and signatures of sequence mutations. The PGDx elio tissue complete assay utilizes a ~1.3 Mb region of interest (ROI) to calculate tumor mutation burden (TMB).

The provided text describes the analytical validation studies for the PGDx elio tissue complete assay, a qualitative in vitro diagnostic device for tumor profiling.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria & Reported Device Performance

The acceptance criteria are generally established as target performance metrics (e.g., call rates, concordance rates, %CV, false positive rates). The reported device performance is the outcome of the analytical studies.

• Accuracy: 582 samples with PGDx elio tissue complete data and orthogonal data. Specifically:
  • SNVs/Indels: 582 samples.
  • ERBB2 Amplifications (FISH comparison): 147 cases (all); 120 cases (excluding borderline).
  • ALK Translocations (FISH comparison): 71 cases. Additional in silico simulation on 10 clinical samples (410 observations).
  • RET Translocations (FISH comparison): 27 cases. 3 RET translocation-positive cell lines also tested.
  • TMB: 118 cases across 8 tumor types.
  • MSI: 283 samples across 18 tumor types.
  • Wild Type Calls: 112 specimens.
• Interlaboratory Reproducibility: 13 FFPE tissue specimens and 1 cell line (14 samples total), tested in duplicate by 2 operators on 12 sequencing runs across 3 non-consecutive days at 3 independent laboratory sites (504 total replicates).
• Lot to Lot Precision: 5 test cases in triplicate across 3 unique kit lots (45 observations).

Data Provenance: The document does not explicitly state the country of origin for the clinical samples. However, it mentions "clinical FFPE specimens," implying real-world patient data. The studies are described in a factual manner, suggesting they are retrospective analyses of collected samples for analytical validation purposes.

3. Number of Experts Used to Establish Ground Truth and Qualifications

The document does not specify the number or qualifications of experts involved in establishing the ground truth for the test set.

Instead, the ground truth for performance evaluation (accuracy) is established by:

• Orthogonal methods:
  • "2 NGS targeted panels" and "PCR" (for SNVs and Indels).
  • "ERBB2 FISH," "ALK FISH," "RET FISH" (for amplifications and translocations).
  • "matched tumor-normal whole exome sequencing results" (for TMB).
  • "MSI PCR" (for MSI).
• Validated assays/literature: For the 3 RET translocation-positive cell lines.

4. Adjudication Method for the Test Set

The document does not describe any expert adjudication process for resolving discrepancies or establishing ground truth for the test set. The ground truth is primarily based on the results from the orthogonal methods. For the in silico studies, the ground truth is derived from down-sampling "clinical samples."

5. MRMC Comparative Effectiveness Study

No multi-reader multi-case (MRMC) comparative effectiveness study was mentioned or performed. This device is a molecular diagnostic assay, not an imaging AI tool, and thus comparative effectiveness with human readers improving with AI assistance is not applicable in this context.

6. Standalone Performance

Yes, the entire document describes studies of the standalone (algorithm only, without human-in-the-loop performance) of the PGDx elio tissue complete assay. The goal is to demonstrate the analytical performance of the automated workflow, from sample preparation to data analysis and variant calling, against established ground truth methods.

7. Type of Ground Truth Used

The primary type of ground truth used is orthogonal methods, specifically:

• Other NGS targeted panels: For SNVs and indels.
• PCR: For certain SNVs/indels and MSI.
• FISH (Fluorescence In-Situ Hybridization): For gene amplifications (ERBB2) and translocations (ALK, RET).
• Whole Exome Sequencing (WES): For Tumor Mutation Burden (TMB).
• Cell line characterization/literature: For known variants in control cell lines.

This is a form of reference standard ground truth, where the device's performance is compared against established, validated measurement techniques.

8. Sample Size for the Training Set

The document details analytical validation (testing) and reproducibility studies. It does not provide information about a "training set" size. As a molecular diagnostic assay, its development likely involves internal data for algorithm development and optimization, but specific training set sizes are not mentioned in this regulatory submission, which focuses on validation data.

9. How the Ground Truth for the Training Set Was Established

Since the document does not discuss a specific "training set" or its size, it also does not describe how ground truth for such a set was established. The focus is on the performance of the final, locked-down algorithm against independent test data with ground truth established by orthogonal methods.

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