(67 days)
Use of BBL Trovafloxacin Sensi-Discs® for in vitro agar diffusion susceptibility testing is indicated when there is a need to determine the susceptibility of bacteria to Trovafloxacin has been shown to be active against most strains of microorganisms listed below, as described in the Roerig package insert for this antimicrobic.
Trovafloxacin Susceptibility Test Discs are prepared by impregnating high guality paper with accurately determined amounts of Trovafloxacin supplied by the manufacturer, Roerig. Each Trovafloxacin disc is clearly marked on both sides with the agent and content. Trovafloxacin discs are furnished in cartridges of 50 discs each. Trovafloxacin cartridges are packed as either a single cartridge in a single box, or in a package containing ten cartridges.
Agar diffusion methods employing dried filter paper discs impregnated with specific concentrations of antimicrobial agents were developed in the 1940's. In order to eliminate or minimize variability in the testing, Bauer et al. developed a standardized procedure in which Mueller Hinton Agar was selected as the test medium.
Various regulatory agencies and standards-writing organizations subsequently published standardized reference procedures based on the Bauer-Kirby method. Among the earliest and most widely accepted of these standardized procedures were those published by the U.S. Food and Drug Administration (FDA) and the World Health Organization (WHO). The procedure was adopted as a consensus standard by the National Committee for Clinical Laboratory Standards (NCCLS) and is periodically updated. The latest NCCLS documents are M2-A6 (1/97) and M100-S7 (1/97).
Discs containing a wide variety of antimicrobial agents are applied to the surface of Mueller Hinton Agar plates {or Haemophilus Test Medium Agar for Haemophilus influenzae or Mueller Hinton Aqar with 5% Sheep Blood for Streptococcus pneumoniae] inoculated with pure cultures of clinical isolates. Following incubation, the plates are examined and the zones of inhibition surrounding the discs are measured and compared with established zone size ranges for individual antimicrobial agents in order to determine the agent(s) most suitable for use in antimicrobial therapy. The determination as to whether the organism in question is susceptible (S), intermediate (I), or resistant (R) to an antimicrobial agent is made by comparing zone sizes to those found in the respective organism tables of National Committee for Clinical Laboratory Standards (NCCLS) Document M2-A6 ("Performance Standards for Antimicrobial Disk Susceptibility tests - Sixth Edition, Approved Standard", 1/97) and of NCCLS Document M100-S8 ("Performance Standards for Antimicrobial Susceptibility Testing", Eighth Informational Supplement, 1/98).
Based on the provided text, here's an analysis of the acceptance criteria and study information for the Trovafloxacin Sensi-Discs:
1. Table of Acceptance Criteria and Reported Device Performance:
The document doesn't explicitly state "acceptance criteria" in a quantitative, pass/fail table format that is typical for modern device submissions. Instead, it relies on alignment with established industry standards for antimicrobial susceptibility testing. The accepted performance is essentially defined by adherence to these standards and the established zone size ranges for Trovafloxacin.
| Performance Metric/Criteria | Reported Device Performance |
|---|---|
| Zone Sizes for Interpretation | Zone sizes used for interpretation of tests, including control organism limits, were determined by the antimicrobic manufacturer, Roerig, a Division of Pfizer Inc., and received FDA approval under NDA Nos. 20-759 and 20-760. The determination as to whether the organism in question is susceptible (S), intermediate (I), or resistant (R) is made by comparing zone sizes to those found in the respective organism tables of National Committee for Clinical Laboratory Standards (NCCLS) Document M2-A6 ("Performance Standards for Antimicrobial Disk Susceptibility tests - Sixth Edition, Approved Standard", 1/97) and NCCLS Document M100-S8 ("Performance Standards for Antimicrobial Susceptibility Testing", Eighth Informational Supplement, 1/98). |
| Standardized Test Procedure Adherence | The device performance implicitly meets the acceptance criteria by conforming to standardized agar diffusion test procedures, specifically those based on the Bauer-Kirby method as adopted by the National Committee for Clinical Laboratory Standards (NCCLS), and documented in M2-A6 (1/97) and M100-S7 (1/97) and M100-S8 (1/98). |
| Activity against specified microorganisms (In Vitro and In Clinical Infections) | Demonstrated activity against the list of microorganisms provided (e.g., Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Haemophilus influenzae, Bacteroides fragilis, Chlamydia pneumoniae, etc.) as described in the Roerig package insert for Trovafloxacin. |
| Activity against specified microorganisms (In Vitro Only) | Demonstrated activity against the list of microorganisms provided for in vitro only (e.g., penicillin-resistant Streptococcus pneumoniae, Citrobacter freundii, Bacteroides distasonis, Mycoplasma hominis, etc.) as described in the Roerig package insert for Trovafloxacin. |
| Product Manufacturing Quality (e.g., accurate amounts of Trovafloxacin, clear marking) | "Trovafloxacin Susceptibility Test Discs are prepared by impregnating high quality paper with accurately determined amounts of Trovafloxacin supplied by the manufacturer, Roerig. Each Trovafloxacin disc is clearly marked on both sides with the agent and content." (This is a description of the product and implicitly a quality criterion). |
2. Sample Size Used for the Test Set and Data Provenance:
The document refers to "Performance Data: See attached Roerig product insert section on Susceptibility Tests - Diffusion Techniques for TROVAN™ Tablets (trovafloxacin mesylate tablets) and TROVAN™ I.V. (alatrofloxacin mesylate injection) for intravenous infusion."
- Sample Size: The specific sample size for the test set is not provided in the excerpt. It defers to the Roerig product insert, which is not included.
- Data Provenance: The document does not specify the country of origin of the data. It seems to refer to data generated by Roerig (a division of Pfizer Inc.), which is a pharmaceutical company. The type of data would be related to clinical trials and in vitro susceptibility testing that formed the basis for the drug's FDA approval (NDA Nos. 20-759 and 20-760). This would implicitly be prospective data collected during the drug's development.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications of those Experts:
This information is not explicitly provided in the excerpt. The ground truth for antimicrobial susceptibility testing, especially for establishing zone size breakpoints, is typically determined through extensive in vitro and in vivo correlation studies, pharmacokinetic/pharmacodynamic modeling, and epidemiological cutoff values. This process involves numerous clinical microbiologists, pharmacologists, and infectious disease specialists, but their specific number and qualifications are not detailed for this submission. The document states that the zone sizes and control organism limits "were determined by the antimicrobic manufacturer, Roerig... and received FDA approval." This implies expert consensus and rigorous review by regulatory bodies.
4. Adjudication Method for the Test Set:
The document does not describe any adjudication method. For antimicrobial susceptibility testing, the "ground truth" (i.e., whether an organism is S, I, or R to an agent) is established by comparing measured zone sizes to predetermined interpretive criteria (breakpoints) set by standardized bodies like the NCCLS, which are themselves derived from extensive studies. It's not a subjective interpretation requiring adjudication in the way medical imaging might.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done:
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done or described. This type of study is highly relevant for subjective diagnostic interpretations (e.g., AI in radiology). Here, the device is a disc for in vitro laboratory testing, not a diagnostic imaging AI. The "readers" are laboratory technicians measuring zone diameters, which is a relatively objective measurement compared to interpreting complex clinical images.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was Done:
The device itself (Trovafloxacin Sensi-Discs) is not an "algorithm" in the AI sense. It's a consumable product used in a manual laboratory procedure.
However, the "performance data" referred to in the Roerig product insert would represent the standalone performance of the antimicrobial agent (Trovafloxacin) in determining susceptibility, based on the established zone size breakpoints. This is a form of standalone performance in that it evaluates the accuracy of the drug's activity and the interpretive criteria, independent of the specific disc manufacturer, as long as the disc meets quality standards (e.g., accurate drug concentration).
7. The Type of Ground Truth Used:
The ground truth used is primarily expert consensus based on extensive in vitro (microbiological) and in vivo (clinical outcomes) correlation data, pharmacokinetic/pharmacodynamic studies, and epidemiological cutoff values. This is distilled into the standardized interpretive criteria (zone size breakpoints) published by organizations like the NCCLS and approved by the FDA (as indicated by the references to NDA approvals for the drug itself). The product relies on the established validity of these breakpoints.
8. The Sample Size for the Training Set:
This information is not provided in the excerpt. The concept of a "training set" in the context of machine learning doesn't directly apply to this device. For the drug itself (Trovafloxacin), the data used to establish its activity profile and breakpoints would have involved a very large number of microbial isolates tested in vitro and patients treated in vivo.
9. How the Ground Truth for the Training Set Was Established:
Similar to point 8, the concept of a "training set" ground truth is not directly applicable. However, for the underlying interpretive breakpoints, the ground truth was established through:
- Clinical Efficacy Studies: For the drug Trovafloxacin, its efficacy against various microorganisms would have been established through clinical trials (human outcomes data).
- Microbiological Studies: Extensive in vitro testing of thousands of bacterial isolates to determine Minimum Inhibitory Concentrations (MICs) and correlate them with zone diameters.
- Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling: Studies to understand how the drug behaves in the human body and how its concentration correlates with bacterial killing.
- Expert Panels: Review and approval by expert committees (e.g., NCCLS, FDA) who synthesize all available data to set the final interpretive criteria (susceptible, intermediate, resistant breakpoints).
§ 866.1620 Antimicrobial susceptibility test disc.
(a)
Identification. An antimicrobial susceptibility test disc is a device that consists of antimicrobic-impregnated paper discs used to measure by a disc-agar diffusion technique or a disc-broth elution technique the in vitro susceptibility of most clinically important bacterial pathogens to antimicrobial agents. In the disc-agar diffusion technique, bacterial susceptibility is ascertained by directly measuring the magnitude of a zone of bacterial inhibition around the disc on an agar surface. The disc-broth elution technique is associated with an automated rapid susceptibility test system and employs a fluid medium in which susceptibility is ascertained by photometrically measuring changes in bacterial growth resulting when antimicrobial material is eluted from the disc into the fluid medium. Test results are used to determine the antimicrobial agent of choice in the treatment of bacterial diseases.(b)
Classification. Class II (performance standards).