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The ACTOnco IVD assay is an in vitro diagnostic test that uses targeted next generation sequencing of formalin-fixed. paraffin-embedded tumor tissue from patients with solid malignant neoplasms to detect genetic alterations in a broad multi gene panel. The test is intended to provide informations, small insertions and deletions, ERBB2 gene amplification, and tumor mutational burden for use by qualified health care professionals in accordance with professional guidelines, and is not conclusive or prescriptive for labeled use of any specific therapeutic product. ACTOnco IVD is a single-site assay performed at ACT Genomics.

The ACTOnco IVD assay is an in-vitro diagnostic assay intended to provide information for use by qualified health care professionals in accordance with professional guidelines, and is not conclusive or prescriptive for labeled use of any specific therapeutic product.

The assay is a custom targeted sequencing platform, utilizing amplicon-based sequencing, to detect point mutations (single nucleotide variants, or SNVs), small insertions and deletions (Indels), ERBB2 gene amplification, and tumor mutational burden (TMB) in tumor specimens. The assay uses custom DNA primers corresponding to all exons and selected introns of oncogenes, tumor suppressor genes, drug metabolism genes, and immune-related genes. Primers are synthesized by a secondary manufacturer (Thermo Fisher Scientific). An overlapping amplicon approach is utilized in which tiled primers are designed to generate multiple overlapping amplicons of the same region to avoid allele dropout. In total, the primers target approximately 1.8Mb of the human genome. Genomic DNA is extracted from FFPE tissue samples.

Sequence libraries are prepared through a multiplex polymerase chain reaction (PCR) amplification step to enrich target sequences. Target sequences are tagged with index oligonucleotide to identify individual sample and adaptor oligonucleotide to anchor the amplicon to complimentary oligonucleotides embedded on the surface of the sequencing bead. Target sequences on the sequencing beads are amplified using emulsion PCR before sequencing. Multiple barcoded sequence libraries (from different patients) are pooled and then sequenced on a Thermo Fisher Ion GeneStudio™ S5 Prime System. Sequence reads are then aligned to the reference human genome. By comparing the identity of bases from the tumor DNA and the reference human genome, variant alterations are identified in the tumor.

The assay system includes a sequencing instrument, reagents (DNA extraction, library preparation and sequencing), software (operation of the sequencing instrument and variant calling), and standard operating procedures (SOPs) for the use of the system. ACT Genomics takes the responsibilities in monitoring the instrument; reagents and consumable materials which will be used in the assay process.

Multiple software components will be used in the assay. The NGS raw read analysis will be done using Thermo Fisher software. Variant calling for SNVs, insertions and deletions will be done using Thermo Fisher software. Mutation and variant annotation will be done using software from ACT Genomics, the Cunningham Lab and Golden Helix software. ERBB2 gene amplification will be done using software from Boeva Lab. Tumor Purity and Zygosity will be done using software from Halgamuge Lab (Kaushalya Amarasinghe). Calculations for tumor mutational burden will be done using ACT Genomics software.

I will analyze the provided text to extract information about the acceptance criteria and the study proving the device meets these criteria. I will then structure this information according to your requested format.

However, based on the provided text, it appears to be a 510(k) summary for a medical device (ACTOnco IVD, a next-generation sequencing-based tumor profiling test). The document describes performance testing (precision/reproducibility, analytical sensitivity/limit of detection, analytical specificity/interference, cross-contamination, DNA input, DNA extraction) and method comparison data.

Crucially, this document
does not contain a direct table of acceptance criteria nor explicit statements about "acceptance criteria" met by the device.

It also does not describe a "Multi Reader Multi Case (MRMC) comparative effectiveness study" or information about "human readers improve with AI vs without AI assistance" as it is a diagnostic test and not an AI-assisted diagnostic imaging device/software for human readers.

Therefore, I will provide the acceptance criteria based on the performance observed in the various analytical validation studies, as these implicitly define the performance considered acceptable for the device. I will also make clear when certain information is not present in the provided text.

Here is the information structured according to your request, extracted from the provided 510(k) summary:

Device: ACTOnco IVD - Next generation sequencing based tumor profiling test

1. Table of Acceptance Criteria (Inferred from Performance Studies) and Reported Device Performance:

Since explicit acceptance criteria are not called out as a separate table, I will infer them from the "Performance Testing" sections, assuming that the reported performance metrics were considered acceptable for the device's clearance.

2. Sample Size and Data Provenance for Test Set:

• Precision/Reproducibility: 20 unique samples (12 single clinical FFPE, 8 pooled DNA from multiple FFPE blocks). Samples covered 10 cancer types.
• Analytical Sensitivity (LoD): 10 different cancer specimens for SNVs/INDELs. For TMB LoD, 5 FFPE tumor specimens. For ERBB2 LoD, 1 amplified sample.
• Analytical Specificity / Interference: 6 FFPE specimens for spike-in (skin, breast, colorectal, endometrial, lung, kidney cancer). 469 specimens for compare-to-similar (necrotic tissue) covering 21 cancer types.
• Cross Contamination: Positive and negative process control samples (specific number not given, but refers to "12 positive control samples alternating with 12 negative control samples within 96-well plate").
• DNA Input: 10 FFPE samples representing 8 cancer types.
• DNA Extraction: Retrospective review of 1526 specimens.
• Method Comparison (SNV/Indels): 438 FFPE samples spanning 21 cancer types.
• Method Comparison (ERBB2 Amplification): 129 FFPE samples spanning 21 cancer types.
• Method Comparison (TMB): 45 FFPE clinical samples covering 14 cancer types.

Data Provenance: The document explicitly states that the samples are "clinical samples (FFPE)" and refer to "various cancer types". It implies that these are real patient samples.
The country of origin is not explicitly stated, but the submitter (ACT GENOMICS Co., LTD) is located in Taipei City, Taiwan. The submission correspondent (K2 Regulatory Consulting, LLC) is in Burlingame, CA, USA. Given that this is an FDA 510(k) submission, the data would typically be representative of the U.S. population or a general population if not geographically specific. The retrospective review of 1526 specimens for DNA extraction likely refers to historical data from ACT Genomics' laboratory.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications:

This information is not explicitly stated in the provided document. For a diagnostic test like this, ground truth is typically established by:

• Comparator Assays: The document states "a well-validated NGS based assay" for SNV/Indels, "HER2 Dual ISH DNA Probe Cocktail test (DISH)" for ERBB2, and "whole exome sequencing (WES)" for TMB. These comparator methods ARE the ground truth.
• Pathology Reports: The presence of FFPE tumor tissue as the specimen type implies pathological confirmation of cancer. Tumor purity is also mentioned, which would involve pathological assessment.

There is no mention of human experts providing consensus reads or establishing ground truth in the way a radiological AI would need.

4. Adjudication Method for the Test Set:

This information is not applicable in the context of this diagnostic test validation, as the ground truth is established by well-defined comparator assays (NGS, DISH, WES) and internal laboratory procedures. There is no indication of multiple human readers or adjudication processes for the results of the assay itself or its comparators in the manner described for imaging studies.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was done, and the effect size of how much human readers improve with AI vs without AI assistance:

No, this type of study was not done. The device (ACTOnco IVD) is a Next Generation Sequencing based tumor profiling test. It is not an AI-assisted diagnostic imaging device/software designed to assist human readers. Therefore, an MRMC study assessing human reader improvement with AI assistance is not applicable to this device.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done:

Yes, the performance studies described are inherently "standalone" in the context of the algorithm's analytical performance. The studies evaluate the device (ACTOnco IVD) as an automated system that performs DNA extraction, sequencing, and variant calling. The "performance testing" sections (Precision/Reproducibility, Analytical Sensitivity, Analytical Specificity, Cross Contamination, DNA Input, Method Comparison) all describe experiments evaluating the accuracy and reliability of the device's output (variant calls, TMB scores, ERBB2 amplification status) compared to reference methods or expected outcomes, without human interpretation of raw data. The human element would primarily be in the final interpretation of the molecular findings by a qualified healthcare professional, as stated in the Indications for Use, "for use by qualified health care professionals in accordance with professional guidelines". The analytical performance itself is algorithm-driven.

7. The Type of Ground Truth Used:

The ground truth for validation was established by:

• Comparator Assays / Gold Standards:
  • For SNVs, MNVs, insertions, and deletions: "a well-validated NGS based assay."
  • For ERBB2 gene amplification: "HER2 Dual ISH DNA Probe Cocktail test (DISH)."
  • For Tumor Mutational Burden (TMB): "whole exome sequencing (WES, next generation sequencing)."
• Internal Controls and Expected Outcomes: For precision, LoD, interference, cross-contamination, and DNA input studies, the ground truth was based on known properties of the samples (e.g., specific variants, dilution levels, known interference composition, or expected wild-type status in controls).
• Pathological Assessment: Implied by the use of FFPE tumor tissue samples and assessment of tumor purity, which would rely on pathological review.

8. The Sample Size for the Training Set:

The document for the 510(k) submission does not specify the sample size for the training set used to develop or train the ACTOnco IVD device. 510(k) summaries primarily focus on the validation (test set) data and may not detail the development/training phase data.

9. How the Ground Truth for the Training Set was Established:

The document does not provide details on how the ground truth for the training set (if any specific training was done for components like variant calling algorithms after initial development) was established. Generally, for NGS panels, training data often involves publicly available genomic datasets, internal curated datasets with orthogonal confirmation (e.g., Sanger sequencing, alternative NGS platforms), and expert pathology review of tissue samples. However, this is speculative as the document is silent on this point.

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