Premier Toxins A&B is a qualitative enzyme immunoassay for the detection of Clostridium difficile toxin A and toxin B in stool from patients with antibiotic associated diarrhea. Premier Toxins A&B is intended for use as an aid in diagnosis of C. difficile associated disease.

Device Description

Premier Toxins A&B is an enzyme immunoassay for the direct detection of Clostridium difficile toxin A and toxin B in stool samples. Breakaway microwells are coated with toxin specific monoclonal and polyclonal antibodies. Diluted patient specimens and HRP-conjugated anti-toxin A and B polyclonal antibodies are added to microwells. If either toxin is present in the diluted patient samples, HRP-conjugated toxin polyclonal antibodies (specific for both toxins) complexes are formed which remain in the microwells after washing. After a final washing step, a substrate / chromagen (urea peroxide and tetramethylbenzidine) is added to the wells. Any bound conjugate converts the substrate / chromagen to a blue color. Addition of acid (Stop Solution) converts the blue to a vellow color.

AI/ML Overview

Here's an analysis of the provided text regarding the acceptance criteria and study for the Premier Toxins A&B device:

The document does not explicitly state pre-defined "acceptance criteria" in terms of specific performance thresholds that the device needed to meet. Instead, it presents the results of a clinical study, implying that these results were considered acceptable for 510(k) clearance by demonstrating substantial equivalence to a predicate device.

1. Table of Acceptance Criteria and Reported Device Performance

As noted, explicit "acceptance criteria" were not listed. However, we can construct a table showing the reported performance statistics from the clinical study. These reported values served as the evidence for substantial equivalence.

Performance Statistic	Reported Value (All Sites)	Implied Acceptance Range/Goal (not explicitly stated, but typically high for medical devices)
Sensitivity	94.7%	High (e.g., >85% or 90%)
Specificity	97.3%	High (e.g., >90% or 95%)
Positive Predictive Value	87.4%	Moderate to High
Negative Predictive Value	98.9%	High (e.g., >95%)
Correlation	96.9%	High

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

Sample Size (Test Set):
- Cytotoxin Positive: 90 (Site 1: 55, Site 2: 35)
- Cytotoxin Negative: 465 (Site 1: 257, Site 2: 208)
- Total Samples (All Sites): 90 + 465 = 555
Data Provenance:
- Country of Origin: United States (stated as "performed at two sites in the United States").
- Retrospective or Prospective: Not explicitly stated, but typically for clinical studies supporting 510(k) in vitro diagnostics, especially for comparison to standard methods, samples might be collected prospectively, or a mix of archived and prospective samples. The document does not provide enough detail to definitively classify it.

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

Ground Truth Method: The ground truth was established by comparison to the "cellular cytotoxicity assay." This is a laboratory-based method, not an expert review of images or clinical data in the human-reader sense.
Number of Experts: Not applicable, as the ground truth was determined by a laboratory assay, not human experts.
Qualifications of Experts: Not applicable.

4. Adjudication Method for the Test Set

Adjudication Method: Not applicable. The "ground truth" was a laboratory reference method (cellular cytotoxicity assay), which has its own established interpretation criteria, not subject to human adjudication in the typical sense of reconciling multiple human readers.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done

MRMC Study: No, an MRMC comparative effectiveness study was not conducted. This study compares the device directly to a laboratory reference method (cellular cytotoxicity assay) using stool samples, not a comparison of human readers with and without AI assistance.

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

Standalone Performance: Yes, this study effectively represents standalone performance. The Premier Toxins A&B device (an enzyme immunoassay) is an automated algorithm-only system in the sense that the test results (color change, absorbance readings) are interpreted by the device's inherent mechanisms to produce a positive or negative result, without direct human intervention in the interpretation of the test itself. The performance statistics (sensitivity, specificity, etc.) are for the device's output compared to the reference standard.

7. The Type of Ground Truth Used

Type of Ground Truth: The ground truth used was a laboratory reference standard: the cellular cytotoxicity assay. This is a well-established method for detecting Clostridium difficile toxins.

8. The Sample Size for the Training Set

The document does not provide any information regarding a "training set" or its sample size. This is common for older 510(k) submissions for in vitro diagnostic devices like ELISAs, which are developed and validated using traditional laboratory methods. The concept of a distinct "training set" and "test set" in the machine learning sense is not explicitly applied here. The clinical study described served as the validation (test) set.

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

Not applicable, as no information on a distinct "training set" is provided.

In summary: The Premier Toxins A&B device demonstrated strong performance (high sensitivity, specificity, and negative predictive value) when compared against the cellular cytotoxicity assay, which served as the gold standard. While explicit numerical acceptance criteria were not stated, the reported performance statistics were deemed sufficient by the FDA for clearance, supporting the device's intended use as an aid in diagnosing C. difficile-associated disease. The study was a standalone validation of the device against a laboratory reference method, not an AI-assisted human reader study.

Summary

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Special 510(k): Device Modification Premier Toxins A&B

K993914

Item II: 510(k) Summary

A. Contacts

Manufacturer: Meridian Diagnostics, Inc. 3471 River Hills Drive Cincinnati, OH 45244 Phone: 513-271-3700 FAX: 513-271-0744

FDA Registration Number:	1524213
Site Contact Person:	Allen Nickol, PhDSenior Director Clinical & Regulatory Affairs & QA
Submission Contact Persons:	David H. Willis, PhDClinical & Regulatory AffairsAllen Nickol, PhDSenior Director Clinical & Regulatory Affairs & QA

Date of Preparation B.

November 12, 1999

C. Name of Device and Classification

Name: Premier Toxins A&B Classification: "Reagents, Clostridium difficile toxin," Class I, LLH.

D. Legally Marketed Device

The predicate (previously cleared) device is the Premier Cytoclone A&B EIA, 510(k) number K911958. Concurrence date was 7/30/91.

E. Device Description

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Intended Use Statement F.

Description of the Technology of the Modified Device Compared to G. Cleared Device

Both devices are microtiter well enzyme immunoassays that involve capture of C. difficile toxins A and B by antibody attached to microtiter wells. Detection is accomplished in both assays using HRP-conjugated antibody. In both assays color change is affected using urea peroxide and tetramethylbenzidine. The differences in protocol and materials do not reflect any fundamental change in technology.

The performance of Premier Toxins A&B was evaluated in a clinical study performed at two sites in the United States. The kit was compared to the cellular cytotoxicity assay .

PremierToxins A&B Results	Cytotoxin Result:Site 1		Cytotoxin Result:Site 2		Cytotoxin Result:All Sites
	Pos	Neg	Pos	Neg	Pos	Neg
Pos	55	7	35	6	90	13
Neg	3	257	2	208	5	465
Performance Statistic	Value	95% CI	Value	95% CI	Value	95% CI
Sensitivity	94.8%	85.6-98.9%	94.6%	81.8-99.3%	94.7%	88.1-98.3%
Specificity	97.3%	94.6-98.9%	97.2%	94.0-99.0%	97.3%	95.4-98.5%
Positive Predictive Value	88.7%	78.1-95.3%	85.4%	70.8-94.4%	87.4%	81.0-93.8%
Negative Predictive Value	98.8%	96.7-99.8%	99.0%	96.6-99.9%	98.9%	97.5-99.7%
Correlation	96.9%	94.4-98.5%	96.8%	93.8-98.6%	96.9%	95.1-98.1%

H. Reproducibility

Souce of Variance	PositiveControl	NegativeControl	HighPositive	MediumPositive	Low Positive	Negative
Mean Absorbance	2.010	0.013	2.250	1.146	0.280	0.009
Within Run CV	4.1%	24.5%	7.3%	6.9%	15.9%	28.9%
Between Run CV	7.0%	16.2%	6.2%	13.9%	14.6%	31.7%

I. Cross-Reactivity

The Premier Toxins A&B test did not cross-react with other known pathogenic bacteria and viruses. Positive reactions were noted with two strains of C. sordellii known to produce the HT and LT homologues to toxins A and B, respectively.

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Image /page/2/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged around the perimeter. Inside the circle is an abstract symbol resembling an eagle or a stylized human figure with outstretched arms.

DEC I 0 1999

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

David H. Willis, Ph.D. Manager, Clinical and Regulatory Affairs Meridian Diagnostics, Inc. 3471 River Hills Drive Cincinnati, Ohio 45244

K993914 Re: Trade Name: Premier Toxins A&B Regulatory Class: I Product Code: LLH Dated: November 16, 1999 Received: November 17, 1999

Dear Dr. Willis:

We have reviewed your Section 510(k) notification of intent to market the device referenced above and we have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.

If your device is classified (see above) into either class II (Special Controls) or class III (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the Current Good Manufacturing Practice requirements, as set forth in the Quality System Regulation (QS) for Medical Devices: General regulation (21 CFR Part 820) and that, through periodic QS inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory action. In addition, FDA may publish further announcements concerning your device in the Federal Register. Please note: this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal laws or regulations.

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Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at (770)488-7655.

This letter will allow you to begin marketing your device as described in your 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll free number (800) 638-2041 or at (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmamain.html"

Sincerely yours.

Steven Butman

Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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Item III: Indications of Use Statement

1993914 510(k) Number (if known):

Device Name: Premier Toxins A&B

Indications For Use:

PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON ANOTHER PAGE IF NEEDED

Concurrence of CDRH, Office of Device Evaluation (ODE)

Woody Dubois

510(k) Number

Prescription Use
(Per 21 CFR 801.109)

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Over-The-Counter Use (Optional Format 1-2-96)

Regulation Number and Section

§ 866.2660 Microorganism differentiation and identification device.

(a)
Identification. A microorganism differentiation and identification device is a device intended for medical purposes that consists of one or more components, such as differential culture media, biochemical reagents, and paper discs or paper strips impregnated with test reagents, that are usually contained in individual compartments and used to differentiate and identify selected microorganisms. The device aids in the diagnosis of disease.(b)
Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.