(246 days)
The BD MAX™ Enteric Parasite Panel performed on the BD MAX™ System is an automated in vitro diagnostic test for the direct qualitative detection of enteric pathogens. The BD MAX Enteric Parasite Panel detects nucleic acids from:
• Giardia lamblia
- · Cryptosporidium (C. hominis and C. parvum only)
- Entamoeba histolytica
Testing is performed on unpreserved or 10% formalin-fixed stool specimens from symptomatic patients with suspected gastroenteritis, enteritis or colitis. The assay is intended to aid in the diagnosis of gastrointestinal infection when used in conjunction with clinical evaluation and other laboratory findings. The test is performed directly on the specimen, utilizing real-time polymerase chain reaction (PCR) for the amplification of specific targets. The test utilizes fluorogenic gene-specific hybridization probes for detection of the amplified DNA.
This test is intended for use, in conjunction with clinical presentation, laboratory findings, and epidemiological information, as an aid in the differential diagnosis of Giardia lamblia, Cryptosporidium hominis and C. parvum, as well as Entamoeba histolytica infections. Results of this test should not be used as the sole basis for diagnosis, treatment, or other patient management decision. Positive results do not rule out co-infection with other organisms that are not detected by this test, and may not be the sole or definitive cause of patient illness. Negative results in the ss compatible with gastroenteritis and/or colitis may be due to infection by pathogens that are not detected by this test or non-infectious causes such as ulcerative colitis, irritable bowel syndrome, or Crohn's disease.
The BD MAX™ System and the BD MAX™ Enteric Parasite Panel are comprised of an instrument with associated hardware and accessories, disposable microfluidic cartridges, master mixes, unitized reagent strips, extraction reagents, and sample buffer tubes. The instrument automates sample preparation including target lysis, DNA extraction and concentration, reagent rehydration, and target nucleic acid amplification and detection using real-time PCR. The assay includes a Sample Processing Control (SPC) that is present in the Extraction Tube. The SPC monitors DNA extraction steps, thermal cycling steps, reagent integrity and the presence of inhibitory substances. The BD MAX™ System software automatically interprets test results. A test result may be called as POS, NEG or UNR for each of the assay's targets, based on the amplification status of the target and of the Sample Processing Control. IND (Indeterminate) or INC (Incomplete) results are due to BD MAX™ System failure.
The provided document describes the analytical and clinical performance of the BD MAX™ Enteric Parasite Panel, an in vitro diagnostic test. The acceptance criteria and device performance are outlined in the "Clinical Performance Studies" section.
Here's a breakdown of the requested information:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state pre-defined acceptance criteria for the clinical performance endpoints in a single, clear table. However, the reported performance metrics (Sensitivity, Specificity, PPA, NPA) for each target and specimen type are presented. For the purpose of this response, I will interpret the reported performance values themselves as the "device performance" and highlight the key metrics that would typically serve as acceptance criteria in such a submission.
| Target & Specimen Type | Performance Metric (Acceptance Criteria Implied) | Reported Device Performance |
|---|---|---|
| Giardia lamblia | ||
| 10% Formalin-Fixed (Prospective) | Sensitivity | 95.5% (95% CI: 78.2%, 99.2%) |
| Specificity | 99.7% (95% CI: 99.1%, 99.9%) | |
| 10% Formalin-Fixed (Retrospective) | Positive Percent Agreement (PPA) | 100.0% (95% CI: 93.5%, 100.0%) |
| Negative Percent Agreement (NPA) | 100.0% (95% CI: 94.9%, 100.0%) | |
| Unpreserved (Prospective) | Sensitivity | 94.4% (95% CI: 74.2%, 99.0%) |
| Specificity | 100.0% (95% CI: 99.4%, 100.0%) | |
| Unpreserved (Retrospective) | PPA | 98.6% (95% CI: 92.6%, 99.8%) |
| NPA | 94.9% (95% CI: 89.8%, 97.5%) | |
| Cryptosporidium parvum/hominis | ||
| 10% Formalin-Fixed (Prospective) | Sensitivity | 90.3% (95% CI: 80.5%, 95.5%) |
| Specificity | 99.8% (95% CI: 99.2%, 99.9%) | |
| 10% Formalin-Fixed (Retrospective) | PPA | 93% (95% CI: 81.4%, 97.6%) |
| NPA | 100% (95% CI: 95.3%, 100%) | |
| Unpreserved (Prospective) | Sensitivity | 100% (95% CI: 90.1%, 100%) |
| Specificity | 99.5% (95% CI: 98.6%, 99.8%) | |
| Unpreserved (Retrospective) | PPA | 97.7% (95% CI: 88.2%, 99.6%) |
| NPA | 98.4% (95% CI: 95.3%, 99.4%) | |
| Entamoeba histolytica | ||
| 10% Formalin-Fixed (Prospective) | Specificity | 100% (95% CI: 99.5%, 100%) |
| 10% Formalin-Fixed (Retrospective) | NPA | 100% (95% CI: 93.4%, 100%) |
| Unpreserved (Prospective) | Specificity | 100% (95% CI: 99.3%, 100%) |
| Unpreserved (Retrospective) | PPA | 100% (95% CI: 74.1%, 100%) |
| NPA | 100% (95% CI: 98.0%, 100%) | |
| Entamoeba histolytica (Contrived) | PPA | 100% (95% CI: 92.9%, 100%) |
| NPA | 100% (95% CI: 92.9%, 100%) | |
| Unresolved Rates (Final) | Max Unresolved Rate (10% FF) | 0.0% (0/1084-0/146) |
| Max Unresolved Rate (Unpreserved) | 1.5% (11/747-0/244) | |
| Indeterminate Rates (Final) | Max Indeterminate Rate (all types) | 0.0% |
| Incomplete Rates (Final) | Max Incomplete Rate (all types) | 0.0% |
2. Sample Size Used for the Test Set and Data Provenance
- Total Compliant Specimens: 2495 (1273 10% formalin-fixed, 1222 unpreserved).
- Split by Type:
- Prospective: 2204 specimens (1128 10% formalin-fixed, 1058 unpreserved, 18 noncompliant - excluded).
- Retrospective: 411 specimens (148 10% formalin-fixed, 251 unpreserved, 12 noncompliant - excluded).
- Excluded from Performance Calculations: 128 retrospective specimens (historical results not confirmed by alternate PCR and bi-directional sequencing).
- Adjusted Compliant Specimens for Performance:
- Giardia lamblia: 1021 (10% Formalin-Fixed Prospective), 126 (10% Formalin-Fixed Retrospective), 673 (Unpreserved Prospective), 209 (Unpreserved Retrospective)
- Cryptosporidium parvum/hominis: 1015 (10% Formalin-Fixed Prospective), 121 (10% Formalin-Fixed Retrospective), 663 (Unpreserved Prospective), 228 (Unpreserved Retrospective)
- Entamoeba histolytica: 827 (10% Formalin-Fixed Prospective), 54 (10% Formalin-Fixed Retrospective), 577 (Unpreserved Prospective), 202 (Unpreserved Retrospective)
- Entamoeba histolytica (Contrived): 100 (50 10% formalin-fixed, 50 unpreserved)
- Data Provenance: The study was a multicenter clinical study with specimens collected as part of routine patient care. It involved five (5) clinical sites and seven (7) collection sites. An internal site also performed testing on specimens from collection centers. The data includes both prospective and retrospective specimens. The country of origin of the data is not explicitly stated, but given the FDA submission, it is likely primarily from the USA, though multi-site studies can include international sites.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
The document describes a "reference method" for establishing ground truth, but does not specify the number or qualifications of experts (e.g., medical technologists, pathologists, or specific specialists) involved in establishing the ground truth.
The "reference method" included:
- Standard microscopic examination (possibly O&P, though not explicitly named as the sole method).
- For confirmed positive specimens, an "alternate PCR and bi-directional sequencing" was used.
- For Giardia lamblia and Cryptosporidium, DFA (Direct Fluorescent Antibody) was also part of the reference method.
- Discrepant analysis involved repeat testing with the alternate PCR and bi-directional sequencing, DFA, EIA (Enzyme Immunoassay), and repeat testing with the BD MAX™ Enteric Panel.
4. Adjudication Method for the Test Set
The document details a discrepant resolution process for the clinical study:
- For specimens where the BD MAX Enteric Parasite Panel result differed from the initial reference method, "discrepant repeat testing" was performed.
- This repeat testing included:
- Alternate PCR and bi-directional sequencing.
- DFA (for Giardia and Cryptosporidium).
- EIA (for Giardia).
- Repeat testing with the BD MAX™ Enteric Panel (often in multiple replicates, e.g., 6 or 12 replicates).
This indicates an adjudication method that goes beyond a simple "x+1" or "x+y" rule, involving multiple different assays and follow-up analysis to establish a confirmed ground truth, particularly for discrepant results. It's a method driven by discrepancy rather than a fixed "consensus" rule initially.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study comparing human readers with and without AI assistance was not mentioned or performed. This device is an automated molecular diagnostic test and does not involve human "readers" in the interpretation of results in the way an imaging AI device would. The BD MAX System itself automates the interpretation of test results.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study
Yes, this entire study can be considered a standalone performance evaluation. The BD MAX™ Enteric Parasite Panel is an automated in vitro diagnostic test, and its performance was evaluated against a reference method (ground truth) without a human-in-the-loop component for the device's operation or result interpretation. The "Test Principle" section explicitly states, "The BD MAX™ System software automatically interprets test results. A test result may be called as POS, NEG or UNR for each of the assay's targets..."
7. Type of Ground Truth Used
The ground truth for the clinical studies was established using a composite reference method consisting of:
- Microscopic examination (implied, given the nature of parasite detection tests, though not explicitly detailed for all cases).
- Alternate PCR and bi-directional sequencing: This is a highly specific molecular method for confirming the presence and identity of the target pathogens.
- Direct Fluorescent Antibody (DFA): Used for Giardia and Cryptosporidium.
- Enzyme Immunoassay (EIA): Used in discrepant analysis for Giardia.
For Entamoeba histolytica, given its rarity, contrived specimens (spiked residual negative clinical specimens) were also used to supplement clinical data for evaluating positive percent agreement.
8. Sample Size for the Training Set
The document does not explicitly state a sample size for a "training set" in the context of machine learning or algorithm development. This device is a real-time PCR assay, and its performance is based on the specificity of its primers and probes and the robustness of the extraction and amplification process, rather than a machine learning model that requires a distinct training set. The "Analytical Inclusivity" and "Analytical Specificity" sections describe testing against known strains and related organisms, which could be considered akin to "training" or "development" data for assay design, but not "training set" in the common AI/ML sense.
9. How the Ground Truth for the Training Set Was Established
As there's no explicitly defined "training set" in the AI/ML sense, there's no ground truth established in that context. However, for the analytical studies (e.g., Limit of Detection, Inclusivity, Specificity), the ground truth was established by:
- Known concentrations of purified organisms: For LoD, organisms were inoculated at specific concentrations into negative stool matrix.
- Known strains/isolates: For inclusivity, specific ATCC strains or known clinical isolates of the target organisms were used.
- Known phylogenetically related species and other organisms: For specificity, a wide range of known bacteria, viruses, parasites, and yeast were tested at specified concentrations.
This involves laboratory-controlled methods, where the "ground truth" (presence/absence and concentration of a specific organism) is inherently known by design.
§ 866.3990 Gastrointestinal microorganism multiplex nucleic acid-based assay.
(a)
Identification. A gastrointestinal microorganism multiplex nucleic acid-based assay is a qualitativein vitro diagnostic device intended to simultaneously detect and identify multiple gastrointestinal microbial nucleic acids extracted from human stool specimens. The device detects specific nucleic acid sequences for organism identification as well as for determining the presence of toxin genes. The detection and identification of a specific gastrointestinal microbial nucleic acid from individuals exhibiting signs and symptoms of gastrointestinal infection aids in the diagnosis of gastrointestinal infection when used in conjunction with clinical evaluation and other laboratory findings. A gastrointestinal microorganism multiplex nucleic acid-based assay also aids in the detection and identification of acute gastroenteritis in the context of outbreaks.(b)
Classification. Class II (special controls). The special controls are set forth in FDA's guideline document entitled: “Class II Special Controls Guideline: Gastrointestinal Microorganism Multiplex Nucleic Acid-Based Assays for Detection and Identification of Microorganisms and Toxin Genes from Human Stool Specimens.” For availability of the guideline document, see § 866.1(e).