Alere™ i Strep A is a rapid, instrument-based, molecular in vitro diagnostic test utilizing isothermal nucleic acid amplification technology for the qualitative detection of Streptococcus pyogenes, Group A Streptococcus bacterial nucleic acid in throat swab specimens obtained from patients with signs and symptoms of pharyngitis. It is intended to aid in the rapid diagnosis of Group A Streptococcus bacterial infections.

All negative test results should be confirmed by bacterial culture because negative results do not prection with Group A Streptococcus and should not be used as the sole basis for treatment.

Device Description

Alere™ i Strep A is a rapid, instrument-based isothermal test for the qualitative detection of Group A Strep from throat swab specimens. The Alere™ i Strep A System utilizes isothermal nucleic acid amplification technology and is comprised of:

. Sample Receiver – single use, disposable containing the elution buffer
. Test Base – single use, disposable comprising two sealed reaction tubes, each containing a lyophilized pellet
Transfer Cartridge – single use, disposable for transfer of the eluted sample to the Test Base, and
Alere™ i Instrument – repeat use reader

The reaction tubes in the Test Base contain the reagents required for Group A Strep bacterial lysis and the subsequent amplification of the target nucleic acid and an internal control. Alere™ i Strep A utilizes a pair of templates (similar to primers) for the specific amplification of DNA from Group A Strep and a fluorescently labeled molecular beacon designed to specifically identify the amplified nucleic acid target. Alere™ i Strep A is performed within the confinement of the Test Base, and no other part of the Alere™ i Instrument has contact with the sample during the amplification process. This reduces the risk of instrument contamination and sample carry-over between measurements.

To perform the assay, the Sample Receiver and Test Base are inserted into the Alere™ i Instrument and the elution buffer is automatically heated by the instrument. The sample is added to the Sample Receiver and transferred via the Transfer Cartridge to the Test Base, resuspending the lyophilized pellets contained within the Test Base and initiating bacterial lysis and target amplification. Heating, mixing and detection by fluorescence is provided by the instrument, with results automatically reported.

Results are displayed by the Alere™ i Instrument and are also stored in an on-board archive and are assigned to a sample ID that has been entered into the Alere™ i Instrument by the operator, and the date/time the test was performed. Data can be retrieved and downloaded by the operator at any time after testing. An external Alere™ Universal Printer can be attached via USB to the Alere™ i Instrument to print test results.

AI/ML Overview

Here's an analysis of the acceptance criteria and the study that proves the device (Alere™ i Strep A) meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

Strict "acceptance criteria" are not explicitly stated in a quantitative manner (e.g., "Sensitivity must be >90%"). However, the clinical study's performance metrics act as the de facto demonstration of acceptable performance for regulatory purposes. The reported performance is what was considered sufficient for substantial equivalence.

Metric	Reported Device Performance (95% CI)
CLINICAL PERFORMANCE
Sensitivity	95.9% (91.4%, 98.1%)
Specificity	94.6% (91.6%, 96.6%)
Positive Predictive Value	88.7% (82.8%, 92.7%)
Negative Predictive Value	98.1% (96.0%, 99.1%)
Initial Invalid Rate	4.8% (3.3%, 7.1%)
Invalid Rate (after re-test)	2.8% (1.7%, 4.8%)
ANALYTICAL PERFORMANCE
Limit of Detection (ATCC 12344)	4.2 CFU/mL (95% detected)
Limit of Detection (ATCC 19615)	41.8 CFU/mL (95% detected)
Reactivity Test (GAP Strains)	All tested strains produced positive results at or near LOD
Cross-Reactivity (33 organisms)	All produced negative results at specified concentrations
Reproducibility (Moderate Pos)	100% agreement (90/90)
Reproducibility (Low Pos)	91.1% agreement (82/90)
Reproducibility (Negative)	100% negative results (90/90)
Reproducibility (High Negative)	94.4% negative results (85/90)

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

Sample Size (Clinical): 481 evaluable throat swab specimens.
Data Provenance: Multi-center, prospective clinical study conducted at 8 US trial sites in 2014.

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

The document does not specify the number or qualifications of experts used to establish the ground truth. It states that the device performance was "compared to bacterial culture," implying independent laboratory analysis, but details about the personnel involved in interpreting these cultures are not provided.

4. Adjudication Method for the Test Set

The document doesn't explicitly describe an "adjudication method" in the typical sense (e.g., 2+1 reader adjudication for imaging studies). For samples with discordant results between the Alere™ i Strep A and the initial bacterial culture, a "laboratory developed real-time PCR assay" was used for further investigation:

Of 18 samples positive by Alere™ i Strep A and negative by bacterial culture, 13 were positive by RT-PCR.
Of 6 samples negative by Alere™ i Strep A and positive by bacterial culture, 4 were negative by RT-PCR.

This suggests that the PCR assay acted as a secondary confirmation method for discordant results, but it's not a formal "adjudication method" agreed upon by multiple human readers in the context of interpretation.

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

No, an MRMC comparative effectiveness study was not done. This device is an in-vitro diagnostic (IVD) test, where performance is typically evaluated against a gold standard (like bacterial culture or PCR), not by comparing human reader performance with and without AI assistance, as would be common for imaging AI.

6. Standalone (Algorithm Only) Performance Study

Yes, the clinical study (and analytical studies) assess the standalone performance of the Alere™ i Strep A device. It's an automated, instrument-based test, meaning its performance is inherently "algorithm only" in the sense that the instrument provides the result without human interpretation of the primary signal. The comparator (bacterial culture) serves as the ground truth.

7. Type of Ground Truth Used

Clinical Study: Bacterial culture was the primary ground truth. For discordant results, a laboratory developed real-time PCR (RT-PCR) assay was used as a secondary method.
Analytical Sensitivity: Defined by the concentration of Group A Strep bacteria producing positive results 95% of the time, determined by testing known bacterial concentrations.

8. Sample Size for the Training Set

The document does not provide information about a separate "training set" for the Alere™ i Strep A. This is typical for IVD devices where the "training" (development and optimization) of the assay is conducted internally by the manufacturer, rather than through publicly documented machine learning training datasets. The presented clinical and analytical studies are validation studies, not training studies.

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

As no separate training set details are provided, the method for establishing its ground truth is also not elaborated. The development of such assays involves extensive internal research, optimization, and verification using characterized bacterial strains and clinical samples, but these are not typically documented as a "training set" in the same way an AI model's training data would be.

Summary

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

ALERE SCARBOROUGH, INC ANGELA DRYSDALE VP, REGULATORY & CLINICAL AFFAIRS 10 SOUTHGATE ROAD SCARBOROUGH ME 04074

March 31, 2015

Re: K141757

Trade/Device Name: Alere i Strep A Regulation Number: 21 CFR 866.2680 Regulation Name: Streptococcus spp. Nucleic Acid-Based Assay Regulatory Class: II Product Code: PGX, OOI Dated: March 9, 2015 Received: March 10, 2015

Dear Ms. Drysdale:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and 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) that do not require approval of a premarket approval application (PMA). 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. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21. Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours,

Uwe Scherf -S for

Sally Hojvat, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K141757

Device Name Alere™ i Strep A

Indications for Use (Describe)

All negative test results should be confirmed by bacterial culture because negative results do not prection with Group A Streptococcus and should not be used as the sole basis for treatment.

Type of Use (Select one or both, as applicable)

Prescription Use (Part 21 CFR 801 Subpart D)
Over-The-Counter Use (21 CFR 801 Subpart C)

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510(K) SUMMARY

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

The assigned 510(k) number is: K141757

SUBMITTER

Alere Scarborough, Inc. 10 Southgate Road Scarborough, ME 04074 Establishment Registration Number: 1221359

CONTACT PERSON

Angela Drysdale (207) 730-5737 (Office) (207) 730-5767 (FAX) Angela.drysdale@alere.com (email)

DATE PREPARED

3/26/2015

TRADE NAME

Alere™ i Strep A

COMMON NAME

Alere™ i Strep, Alere™ i, Alere™ Strep A

CLASSIFICATION NAME

Groups A, C and G Beta Hemolytic Streptococcus Nucleic acid Amplification System (per 21 CFR 866.2680) Real Time Nucleic Acid Amplification System (per 21 CFR 862.2570)

CLASSIFICATION Class II

PRODUCT CODE PGX, 00I

PANEL Microbiology (83)

PREDICATE DEVICE Lyra Direct Strep Assay, K133883

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DEVICE DESCRIPTION

. Sample Receiver – single use, disposable containing the elution buffer
. Test Base – single use, disposable comprising two sealed reaction tubes, each containing a lyophilized pellet
Transfer Cartridge – single use, disposable for transfer of the eluted sample to the Test Base, and
Alere™ i Instrument – repeat use reader

INTENDED USE

Alere™ i Strep A is a rapid, instrument-based, molecular in vitro diagnostic test utilizing isothermal nucleic acid amplification technology for the qualitative detection of Streptococcus pyogenes, Group A Streptococcus bacterial nucleic acid in throat swab specimens obtained from patients with signs and symptoms of pharvngitis. It is intended to aid in the rapid diagnosis of Group A Streptococcus bacterial infections.

All negative test results should be confirmed by bacterial culture because negative results do not preclude infection with Group A Streptoccus and should not be used as the sole basis for treatment.

TECHNOLOGICAL CHARACTERISTICS

Alere™ i Strep A and the predicate device, Lyra Direct Strep Assay, have the same intended use, indications for use, and utilize similar basic principles of operation. They are both molecular tests for the qualitative detection of Group A Strep nucleic acid.

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DEVICE COMPARISON

Parameter	Alere™ i Strep A	Lyra Direct Strep Assay (K133883)
FDA Product Code	PGX, OOI	Same
Assay Target	Streptococcus pyogenes	Streptococcus pyogenes , pyogenic Group C and Gß-hemolytic Streptococcus
Intended Use	Alere™ i Strep A is a rapid, instrument-based, molecular in vitro diagnostic test utilizing isothermal nucleic acid amplification technology for the qualitative detection of Streptococcus pyogenes , Group A Streptococcus bacterial nucleic acid in throat swab specimens obtained from patients with signs and symptoms of pharyngitis. It is intended to aid in the rapid diagnosis of Group A Streptococcus bacterial infections.All negative test results should be confirmed by bacterial culture because negative results do not preclude infection with Group A Streptococcus and should not be used as the sole basis for treatment,	The Lyra Direct Strep Assay is a Real-Time PCR in vitro diagnostic test for the qualitative detection and differentiation of Group A ß-hemolytic Streptococcus ( Streptococcus pyogenes ) and pyogenic Group C and G ß-hemolytic Streptococcus nucleic acids isolated from throat swab specimens obtained from patients with signs and symptoms of pharyngitis, such as sore throat. The assay does not differentiate between pyogenic Groups C and G ß-hemolytic Streptococcus .All negative test results should be confirmed by bacterial culture, because negative results do not preclude Group A, C or G Strep infection and should not be used as the sole basis for treatment.The assay is intended for use in hospital, reference, or state laboratory settings. The device is not intended for point-of-care use.
Instrumentation	Alere™ i Instrument	ABI 7500 Fast DX Thermocycler
Assay Information
Sample Type	Throat Swab	Same
Target Analyte	Group A Streptococcus( Streptococcus pyogenes )	Group A Streptococcus ( Streptococcus pyogenes )Groups C and G Streptococcus
Technology	Isothermal nucleic acid amplification	Multiplex Real-time PCR
Internal Control	Yes	Same
Result	Automated	Same
Interpretation
Assay Result	Qualitative	Same
Time to Result	< 8 minutes	<70 minutes after extraction

Alere™ i Strep A was compared to the legally marketed predicate device, the Lyra Direct Strep Assay.

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PERFORMANCE SUMMARY

CLINICAL STUDY

The clinical performance of Alere™ i Strep A was established in a multi-center, prospective clinical study conducted at 8 US trial sites in 2014.

A total of 481 evaluable throat swab specimens, collected from patients of all ages presenting with symptoms of pharyngitis, were evaluated with Alere™ i Strep A, and compared to bacterial culture. Sixty-two percent (62%) of the population tested was female and 38% was male.

In this study, two (2) throat swabs were collected from each of 481 patients. One throat swab from each patient was tested with Alere™ i Strep A. The other throat swab was sent to a laboratory for bacterial culture.

Alere™ i Strep A performance, including 95% confidence intervals, versus bacterial culture is provided below.

Alere™ i Strep A Performance vs. Culture (All Age Groups Combined)

	Culture +	Culture -
Alere™ i +	141	18a	159
Alere™ i -	6b	316	322
	147	334	481

Sensitivity: 141/147 = 95.9% (95% CI = 91.4% 98.1%) Specificity: 316/334 = 94.6% (95% CI = 91.6%, 96.6%) Positive Predictive Value = 141/159 = 88.7% (82.8%, 92.7% Negative Predictive Value = 316/322 = 98.1% (96.0%, 99.1%)

a Of the 18 samples positive by Alere™ i Strep A and negative by bacterial culture, 13 were also positive for Group A Strep by a laboratory developed real-time PCR assay and © of the 6 samples negative by Alere™ i Strep A and positive by bacterial culture, 4 samples were also negative for Group A Strep by a laboratory developed real-time PCR assay.

During the prospective clinical study, the initial invalid rate (before repeat testing per the product instructions) was 4.8% (24/495) (95% Cl: 3.3%, 7.1%). After repeat testing per the product instructions, the invalid rate was 2.8% (14/495) (95% CI: 1.7%, 4.8%).

ANALYTICAL STUDIES

ANALYTICAL SENSITIVITY

Alere™ i Strep A limit of detection (LOD or C55), defined as the concentration of Group A strep bacteria that produces positive Alere™ i Strep A results approximately 95% of the time, was identified by evaluating different concentrations of 2 strains of Group A Strep in Alere™ i Strep A . The concentrations identified as the LOD (or C95) levels for each strain tested are listed below.

Group A Strep Strain	Concentration(CFU/mL ofElution Buffer)	# DetectedperTotal Tests	% Detected
ATCC 12344	4.2	19/20	95%
ATCC 19615	41.8	19/20	95%

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REACTIVITY TESTING

The following Group A Strep strains were tested and produced positive results at or near the stated assay limit of detection of the Alere™ i Strep A test: ATCC8135, ATCC12384, ATCC12203, ATCC12204, ATCC12365, ATCC14289, ATCC49399, ATCC51339, ATCC700294, ATCC12357, ATCC12385 (Loomis), ATCC 12385 (Type 4).

ANALYTICAL SPECIFICITY (CROSS-REACTIVITY)

To determine the analytical specificity of Alere™ i Strep A, 33 commensal and pathogenic microorganisms (32 bacteria and 1 yeast) that may be present in the throat were tested. All of the following microorganisms and yeast produced negative results when tested at concentrations ranging from 106 to 109 cells/mL of Elution Buffer.

Bacteria

Yeast

Candida albicans Arcanobacterium haemolyticum1 Bacillus cereus Bordetella pertussis Burkholderia cepacia Campylobacter rectus Corynebacterium diphtheria Enterococcus faecalis Escherichia coli Fusobacterium necrophorum Haemophilus influenzae Klebsiella pneumoniae Lactobacillus acidophilus Moraxella catarrhalis1,2 Neisseria gonorrhoeae Peptostreptococcus micros Prevotella (Bacteroides) oralis1 Pseudomonas aeruginosa Staphylococcus aureus Staphylococcus epidermidis Streptococcus agalactiae Streptococcus aginosus Streptococcus canis Streptococcus dysgalactiae subsp equisimilis Streptococcus gallolyticus Streptococcus intermedius Streptococcus mitis Streptococcus mutans Streptococcus pneumoniae Streptococcus salivarius Streptococcus sanguinis Treponema denticola Veillonella parvula 1Invalid results obtained at >106 cells/mL of Elution Buffer 2One false-positive result obtained a >108 cells/mL of Elution Buffer

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INTERFERING SUBSTANCES

The following substances, naturally present in throat swab specimens or that may be artificially introduced into the throat, were evaluated with Alere™ i Strep A at the concentrations listed below and were found not to affect test nerformance.

Substance	Concentration
Whole Blood	5% (v/v)
Mucin	0.016% (w/v)
Human Saliva	10% (v/v)
Ibuprophen	15.4 mg/mL
Acetaminophen	19.4 mg/mL
Acetylsalicylic acid	12.4 mg/mL
Albuterol	0.5 mg/mL
Diphenhydramine HCL	2.7 mg/mL
Cepacol® Sore Throat Lozenges - cherry	20% (w/v)
Sucrets® Sore Throat & Cough - cherry	20% (w/v)
Halls Plus® - Honey Lemon	20% (w/v)
ACT® Total Care - Fresh Mint	20% (v/v)
Cepacol® Mouthwash	20% (v/v)
Listerine® Antiseptic Mouthwash - Original	20% (v/v)
Crest® Complete Multi-Benefit Whitening +Deep Clean Toothpaste	0.16% (w/v)
Zicam® Oral Mist - arctic mint	20% (v/v)
Chloraseptic® Max Sore Throat Relief +Coating Action - wild berry	20% (v/v)
Contact Cold & Flu Tablets - Night	20% (w/v)
Robitussin® Maximum Strength NighttimeCough DM	20% (v/v)
Tylenol® Cold Multi-Symptom Liquid	20% (v/v)
Children's Dimetapp® Cough & Cold	20% (v/v)

When Mucin was tested at a concentration of 2%, 0.4%, and 0.08%, false negative results were observed.

When Crest® Complete Multi-Benefit Whitening + Deep Clean Toothpaste were tested at 20% and 4% invalid results were observed. Additionally, false negative results were observed when tested at a concentration of 0.8%.

REPRODUCIBILITY

A reproducibility study of Alere™ i Strep A was conducted by operators from 3 sites using panels of blind coded specimens containing negative (below the limit of detection), low positive (~3X limit of detection), and moderate positive (~19X the limit of detection) Group A Strep bacterial samples. Participants tested multiple samples of each panel member on 5 different days. The percent agreement with expected results for the Strep A moderate positive and low positive samples were 100% (90/90) and 91.1% (82/90). All of the negative samples (90) generated negative test results as did 94.4% (85/90) high negative samples. There were a total of 5 invalid results on initial testing (5/360 samples; 1.4%). There were no significant differences within run (replicates tested by one operator'), between run (5 different days), between sites (3 sites), or between operators (6 operators).

The results of the analytical and clinical studies performed with Alere™ i Strep A support the determination of substantial equivalence in accordance with the stated intended use and device labeling.

Regulation Number and Section

§ 866.2680

Streptococcus spp. nucleic acid-based assay.(a)
Identification. AStreptococcus spp. nucleic acid-based assay is a qualitative in vitro diagnostic device intended to simultaneously detect and identify variousStreptococcus spp. nucleic acids extracted directly from clinical specimens. The device detects specific nucleic acid sequences for organism identification. The identification aids in the diagnosis of diseases caused by bacteria belonging to the genusStreptococcus and provides epidemiological information on these diseases. Pathogenic streptococci are associated with infections, such as sore throat, impetigo (an infection characterized by small pustules on the skin), urinary tract infections, rheumatic fever, and kidney disease.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include detailed device description documentation, including the device components, ancillary reagents required but not provided, and a detailed explanation of the methodology including primer/probe sequence, design, and rationale for sequence selection.
(2) Premarket notification submissions must include detailed documentation from the following analytical and clinical performance studies: Analytical sensitivity (Limit of Detection), reactivity, inclusivity, precision, reproducibility, interference, cross reactivity, carry-over, and cross contamination.
(3) Premarket notification submissions must include detailed documentation from a clinical study. The study, performed on a study population consistent with the intended use population, must compare the device performance to results obtained from well-accepted reference methods.
(4) Premarket notification submissions must include detailed documentation for device software, including, but not limited to, software applications and hardware-based devices that incorporate software.
(5) Premarket notification submissions must include database implementation methodology, construction parameters, and quality assurance protocols, as appropriate.
(6) The device labeling must include limitations regarding the need for culture confirmation of negative specimens, as appropriate.
(7) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling.
(8) Premarket notification submissions must include details on an end user device training program that will be offered while marketing the device, as appropriate.