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MDx-Chex for BCID2 is intended for use as an external positive and negative assayed control to monitor the performance of the qualitative detection of yeast, Gram positive and Gram negative bacteria, as vell as snciated antimicrobial resistance genes, by the BioFire FilmArray Blood Culture Identification 2 (BCID2) Panel on FilmArray systems. Control 1 - GN: Gram negative bacteria: Acinetobacter colcacer in complex, Baceronides fragilis, Enterobacter cloacae complex, Escherichia coli, Klebsiella oxytoca, Klebsiella oxytoca, Klebsiella pneumats Jray, Proteus spp., Salmonella spp., Serratia marcescens, Heisseria vivoca, Neisseria meningitides, Poeudnonas aeruginosa, Stenotrophomonas matophilia; antimicrobial resistance genes: KPC, CTX-M, IMP, NDM, OXA-Ike, VIM, mcr- 1. Control 2 - GPY: Gram positive bacteria: Enterococcus face: 11, 27712-10, nr., iUDM, U.Steria monocytogenes, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus lugdumsis, Streptococcus agalactiae, Streptococcus pneumonia, Streptococcus pyogenes; yeast: Candida dhicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans/gatit; animicrobial resistance genes mecA/C and MREJ, vanA/B. This product is not intended to replace manufacturer controls provided with the device.

MDx-Chex for BCID2 Control 1 - GN is positive for certain pathogens and antimicrobial resistance genes in the FilmArray BCID 2 panel and negative for those contained in MDx-Chex for BCID2 Control 2 - GPY. MDx-Chex for BCID2 Control 2 - GPY is positive for the remaining pathogen and antimicrobial resistance genes and negative for those present in MDx-Chex for BCID2 Control 1 - GN (see Table 1 below). Each control mix also contains and controls for blood and blood culture media components that have been identified as PCR inhibitors namely hemoglobin, leukocyte DNA, and anticoagulants. MDx-Chex for BCID2 is a quality control containing stabilized blood components, blood culture media components, and inactivated microorganisms resulting in a full-process, cellular-based control for the BioFire BCID2 Panel. Use of full-process cellular controls are necessary to evaluate the entire analytical process, including sample lysis, nucleic acid isolation and purification, amplification, detection, and analysis, as well as the impact of PCR inhibitors and preanalytical variables. Routine use of full process quality controls can help identify variations in the test system that can lead to incorrect results.

This document describes the performance of a quality control material (MDx-Chex for BCID2) for a qualitative detection assay (BioFire FilmArray Blood Culture Identification 2 (BCID2) Panel). Therefore, the "acceptance criteria" and "device performance" are related to the ability of this quality control material to consistently produce expected positive and negative results when tested with the BCID2 panel, along with its stability under various conditions.

The provided document describes a series of performance studies for the MDx-Chex for BCID2 device. Since this is a quality control material and not a diagnostic device that interprets clinical images or data, many of the typical acceptance criteria and study design elements of AI/ML-based diagnostic devices (e.g., number of experts, adjudication methods, MRMC studies) are not applicable here.

Here's an analysis based on the information provided, focusing on the relevant criteria for a quality control material:

1. Table of Acceptance Criteria and the Reported Device Performance:

The acceptance criterion across all relevant studies (Multi-Site Precision, Single-Site Precision, Lot-to-Lot Reproducibility, Closed-Vial Stability, Open-Vial Stability, Shipping Stability) is "overall positive and negative percent agreement of ≥ 95%" (except for Lot-to-Lot Reproducibility which states "≥ 90%").

2. Sample size used for the test set and the data provenance:

• Multi-Site Precision (Reproducibility):
  • Sample Size: 10 samples per control level (20 samples total per lot) were tested over 10 days at each of 4 sites. Three lots were used, totaling 240 expected results for positive agreement (4 sites * 20 samples/lot * 3 lots). The narrative indicates "230/240" for observed positive results and "239/240" for negative results (which means 240 expected negative results reported).
  • Data Provenance: Prospective. Collected internally at Streck (La Vista, NE) and externally at UNMC (Omaha, NE), Children's Hospital and Medical Center (Omaha, NE), and Mary Lanning Healthcare (Hastings, NE). All locations are in the USA.
• Single-Site Precision (Repeatability):
  • Sample Size: 20 samples per lot per level were tested by four operators over 20 non-consecutive days. Three lots were used. This totals 120 expected results for positive agreement (20 samples/lot/level * 2 levels * 3 lots, if pooling levels/lots for the single site precision table, or 2023 = 120 positive AND 120 negative). The table shows 114/120 for positive and 120/120 for negative.
  • Data Provenance: Prospective. Collected at Streck (La Vista, NE), USA.
• Lot-to-Lot Reproducibility:
  • Sample Size: 6 samples per control lot and level (12 total samples per lot). Three lots were tested. A total of 36 complete runs were generated. The tables show 12 expected results per lot for positive and negative agreements (12 expected positive results + 12 expected negative results, repeated for 3 lots).
  • Data Provenance: Prospective. Likely collected at Streck (La Vista, NE), USA, as it states "Data from the first 6 timepoints in the repeatability study above were also used".
• Closed-Vial Stability:
  • Sample Size: 10 samples per control lot and level. Three lots. Tested at Day 0 (baseline) and at least Day 61. For Day 0, 120 tubes were completed. For Day 61+, 60 tubes per storage condition (2-8°C and 20-25°C) across the three lots were tested.
  • Data Provenance: Prospective. Likely collected at Streck (La Vista, NE), USA.
• Open-Vial Stability:
  • Sample Size: Same as Closed-Vial Stability, 10 samples per lot per level, three lots, same time points.
  • Data Provenance: Prospective. Likely collected at Streck (La Vista, NE), USA.
• Matrix Effect:
  • Sample Size: Triplicate tests (3/3) for each matrix type (MDx-Chex positive, Clinical positive, MDx-Chex negative, Clinical negative).
  • Data Provenance: Prospective. Likely collected at Streck (La Vista, NE), USA.
• Shipping Stability:
  • Sample Size: Two sets of samples from one control lot were used. Ten samples of Control 1 and Control 2 were tested for each temperature profile (Summer, Winter). This results in 20 expected positive results and 20 expected negative results per temperature profile.
  • Data Provenance: Prospective. Likely collected at Streck (La Vista, NE), USA.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

Not applicable. This is a quality control material where the "ground truth" is the expected positive or negative result for the specific analytes contained or not contained within the control sample, based on its formulation. The performance is assessed by how consistently the QC material produces these known results when run on the target diagnostic system (BioFire FilmArray BCID2 Panel).

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set:

Not applicable. As noted above, the "ground truth" is inherent to the formulation of the quality control material itself (i.e., it is designed to be positive for certain targets and negative for others). Where initial false results occurred, the "correct results upon a single retest" are noted, which implies a re-run of the test and confirms the expected outcome for the control. This is a standard practice in QC testing to ensure an isolated error vs. a systemic issue.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

Not applicable. This is not an AI/ML diagnostic device for human interpretation. It's a quality control material for an automated molecular diagnostic assay.

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

The device (MDx-Chex for BCID2) is a physical control material. Its "standalone" performance is assessed by how accurately the BioFire FilmArray BCID2 Panel (the primary device it controls) identifies the known positive and negative components within the MDx-Chex material. The studies listed demonstrate this "standalone" performance of the control material with the primary diagnostic system. There is no "algorithm" per se being evaluated in terms of its diagnostic accuracy on clinical cases.

7. The type of ground truth used:

• Formulation-based Ground Truth: The ground truth for this quality control material is established by its known composition. The MDx-Chex for BCID2 Controls are manufactured to contain specific inactivated microorganisms and antimicrobial resistance genes (for positive results) or to be free of certain targets (for negative results), as detailed in Table 1 (pages 4-5).
• For the "Matrix Effect" study, "inactivated Streptococcus pneumoniae was spiked into the control matrix" and "into a BD BACTEC Plus Aerobic/F culture bottle with negative whole blood to simulate a clinical samples". The expected results are thus inherently known based on the spiking.

8. The sample size for the training set:

Not applicable in the conventional sense of training an AI/ML model for diagnostic purposes. This is a manufactured chemical/biological control product. Its "training" equivalent would be the R&D and manufacturing processes to ensure its consistent composition and stability. However, if looking for manufacturing lots/batches rather than a statistical training set: Most studies used three separately manufactured lots of the control material (Lot 20363, Lot 20366, Lot 21129) to demonstrate reproducibility and stability.

9. How the ground truth for the training set was established:

Not applicable as it's not an AI/ML model with a discrete training set. The "ground truth" for the characteristics of the product itself would be established through its design specifications, formulation, and in-house characterization during manufacturing.

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Cell-Free DNA BCT is a direct-draw venous whole blood collection device intended for the collection, and transport of venous whole blood samples for use in conjunction with cell-free DNA next-generation sequencing liquid biopsy assays that have been cleared or approved for use with samples collected in the Cell-Free DNA BCT device.

Cell-Free DNA BCT is a sterile, single use, direct-draw blood collection tube comprised of 3 components (i.e. glass tube with rubber stopper, anticoagulant, and cell preservatives). The blood collection tube manufactured with USP Type III glass containing cerium oxide (to prevent color change associated with gamma irradiation). Each tube includes 200 uL ± 10% of liquid reagent composition includes an anticoagulant K3EDTAand a preservative.

The device is intended to be placed inside a tube holder or an adaptor that contains a needle designed to pierce the tube closure and allow blood to flow into the tube. Once the vein has been penetrated blood collection needle or a blood collection set), the tube is pushed into the holder, and the blood enters the tube. Once a tube has drawn the appropriate amount of blood (10 mL), it is disengaged from the holder and inverted 10 times to mix the blood. The specimen is then transported to the lab for plasma isolation and extraction of cfDNA.

This response describes the acceptance criteria and study details for the Cell-Free DNA BCT device, as outlined in the provided text.

Acceptance Criteria and Device Performance

The provided document does not explicitly present a consolidated table of acceptance criteria with corresponding reported device performance for all studies. Instead, acceptance is implied through successful outcomes of various analytical performance studies. The core acceptance criteria revolve around the ability of the Cell-Free DNA BCT to preserve cfDNA concentration, size, and integrity, and to maintain variant call concordance (Positive Percent Agreement - PPA and Negative Percent Agreement - NPA) in comparison to a reference or within defined variations. Specific numerical acceptance thresholds are often redacted (marked as "(b) (4)") in the provided text.

Here’s a table summarizing the reported device performance based on the described studies, with acceptance implied by the positive conclusions of the FDA.

Study Details

2. Sample Size Used for the Test Set and Data Provenance

• Repeatability (Within-lot variability): 33 patients with advanced stage solid tumors. Each subject provided blood for 4 Cell-Free DNA BCTs from a single lot. Prospective data collection.
• Reproducibility (Lot-to-lot variability): 30 patients with advanced stage solid tumors. Blood was drawn into Cell-Free DNA BCTs representing 3 different lots. Prospective data collection.
• Shelf-life: 30 healthy subjects. Blood collected into tubes tested at various timepoints (T0, T8.5, T12.5, T18.5, T24.5 months) and pre-collection storage temperatures (2, 22, or 30°C). Prospective data collection.
• Preservative interference: 12 subjects with advanced stage solid tumors. Three venous whole blood specimens collected into candidate devices (reference, 2x Preservative A, 2x Preservative B). Prospective data collection.
• Incomplete Mixing: Patients with advanced stage solid tumors (specific number not given, but likely similar to other studies, potentially 12 from context of preservative study). Three Cell-Free DNA BCTs per subject (10, 5, or 15 inversions). Prospective data collection.
• Short Draw: 15 subjects with advanced stage solid tumors. Three Cell-Free DNA BCTs per subject, reflecting normal, 2x Reagent (5mL blood), or (b)(4) Reagent ((b)(4) blood) fill volumes. Prospective data collection.
• cfDNA Stability (device aged): Patients with advanced stage solid tumors (specific number not given). Four Cell-Free DNA BCTs per patient (two reference from youngest lot, one from 8 months, one from 17 months post-manufacture). Prospective data collection.
• Post-Collection Storage of Venous Whole Blood: 30 healthy subjects. Eight tubes per donor (4 K2EDTA, 4 Cell-Free DNA BCTs) tested under various storage conditions (Day 0 immediate, Day 7 at (b)(4) or (b)(4)). Prospective data collection.
• Pre-collection storage and Post-collection storage impacts on Guardant360 CDx assay performance: Whole blood specimens from patients with advanced stage solid tumors (specific number not given). Cell-Free DNA BCTs manufactured at various time points (T0, T3.2, T7.2, T12.2, T18.2, T24.2 months) and BCTs stored at extreme temperatures before collection. Plasma isolated after 1 or 7 days post-collection. Prospective data collection.
• Cell-Free DNA BCT vs. K2EDTA BCT Concordance: 59 patients (non-small cell lung cancer Stage III or IV, pre-screened for CDx variants). Two K2EDTA BCTs and two Cell-Free DNA BCTs collected per patient. Three tubes were processed for the study (one K2EDTA, two Cell-Free DNA BCTs). Prospective data collection. All data appears to be US (country of origin for Guardant Health) and primarily prospective, involving clinical subjects or healthy donors for specific studies.

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

The document does not explicitly state the number or qualifications of experts used to establish ground truth. For studies involving variant call concordance, the "ground truth" for the performance metrics (PPA, NPA, APA, ANA) would be derived from the Guardant360 CDx assay (P200010), which is a cleared/approved next-generation sequencing liquid biopsy assay. The internal analysis of these assay results would be performed by qualified laboratory personnel at Guardant Health, but "experts" in the sense of independent clinical reviewers for ground truth are not mentioned as part of these specific analytical studies. The ground truth is the molecular profile determined by the Guardant360 CDx assay itself.

4. Adjudication Method for the Test Set

Adjudication methods for establishing ground truth from multiple readers/methods are not applicable (N/A) in this context. The "ground truth" for each specific experiment is defined by the results obtained from the reference condition or the established Guardant360 CDx assay. Variant call agreements (PPA, NPA, APA, ANA) are calculated by comparing results from different conditions to each other or to a pre-defined reference condition within the study design, not by external expert adjudication of conflicting results.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No MRMC comparative effectiveness study was described. This device is a blood collection tube, and the studies focus on its analytical performance and impact on downstream assay results, not on human reader interpretation of diagnostic images or data. The impact is assessed on the molecular analysis carried out by the Guardant360 CDx assay.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

Yes, all presented performance studies are "standalone" in the sense that they evaluate the analytical performance of the device (Cell-Free DNA BCT) in preserving cfDNA and enabling accurate results from the Guardant360 CDx assay. The performance metrics (PPA, NPA, APA, ANA, cfDNA concentration, integrity) are objective measurements derived from the molecular assay, not contingent on human interpretation in the loop with the device itself. The Guardant360 CDx assay itself is an "algorithm only" type of test in that its result is a molecular profile.

7. Type of Ground Truth Used

The primary type of "ground truth" used across these studies is the molecular profile/variant calls generated by the Guardant360 CDx assay (P200010).

• For repeatability and reproducibility, variant calls from replicate tubes serve as a comparison point.
• For preservative, mixing, and short draw interference studies, variant calls from a reference condition (e.g., normal preservative, 10 inversions, full draw) serve as the ground truth against which experimental conditions are compared using PPA and NPA.
• For shelf-life and cfDNA stability studies, cfDNA concentration, size, integrity, and variant call concordance (PPA/NPA) against a Day 0 or youngest-lot reference are used.
• For method comparison, concordance is established against the K2EDTA BCT, which was used to acquire samples for the clinical studies supporting Guardant360 CDx. This implies K2EDTA's performance is currently accepted, making it a de-facto reference.

8. The Sample Size for the Training Set

The document describes performance evaluation studies and does not mention "training sets" as it would for a typical AI/ML algorithm development. This device is a blood collection tube with specific chemical and physical properties aimed at sample preservation, not a diagnostic algorithm that requires training. Therefore, N/A for training set sample size.

Given that the performance is assessed using the Guardant360 CDx assay, it can be inferred that the assay itself would have its own extensive training and validation datasets, but these are not for the Cell-Free DNA BCT device specifically.

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

As noted above, there is no "training set" for the Cell-Free DNA BCT device. The performance is based on analytical studies. N/A.

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