Alere i Strep A 2 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.

Device Description

Alere™ i Strep A 2 is a rapid, instrument-based isothermal test for the qualitative detection of Streptococus pyogenes Group A Strep from throat swab specimens. The Alere™ i Strep A 2 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 Streptococcus pyogenes Group A Strep bacterial lysis and the subsequent amplification of the target nucleic acid and an internal control. Alere™ i Strep A 2 utilizes a pair of templates (similar to primers) for the specific amplification of DNA from Streptococcus pyggenes, Group A Strep and fluorescently labeled molecular beacons designed to specifically identify the amplified nucleic acid targets. Alere™ i Strep A 2 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. The sample is added to the Sample Receiver and 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 a summary of the acceptance criteria and study details for the Alere™ i Strep A 2 device, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The FDA clearance document doesn't explicitly state all "acceptance criteria" as clear numerical thresholds for performance metrics. However, it presents the clinical performance of the device against a comparator method (bacterial culture), and these reported values implicitly demonstrate that the device met the necessary performance expectations for clearance.

Performance Metric	Acceptance Criteria (Implied by Clearance)	Reported Device Performance (Alere™ i Strep A 2 vs. Culture)
Clinical Sensitivity	High (specific threshold not stated)	98.5% (95% CI = 95.6%, 99.5%)
Clinical Specificity	High (specific threshold not stated)	93.4% (95% CI = 91.4%, 94.9%)
Positive Predictive Value	High (specific threshold not stated)	78.9% (95% CI = 74.3%, 83.6%)
Negative Predictive Value	High (specific threshold not stated)	99.6% (95% CI = 98.3%, 99.9%)
Initial Invalid Rate	Low (specific threshold not stated)	0.9%
Invalid Rate (after retest)	Very Low (specific threshold not stated)	0.4%
Analytical Sensitivity (LOD)	Specific concentrations for each strain	ATCC 12344: 147 cells/mL (100% Detected) ATCC 19615: 25 cells/mL (95% Detected)
Reactivity	Positive results for tested strains	All listed strains produced positive reactions
Analytical Specificity (Cross-Reactivity)	Negative results for tested microorganisms	All listed microorganisms and yeast produced negative results
Interfering Substances	No effect on test performance	Most substances showed no effect; few instances of false-negative/positive at higher concentrations
Reproducibility (low/moderate positive)	100% agreement with expected results	100% (90/90) agreement
Reproducibility (negative)	100% negative results	100% (90) negative results

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

Sample Size (Clinical Study): 981 evaluable throat swab specimens.
Data Provenance: Multi-center, prospective clinical study conducted at nine (9) US trial sites in 2017.

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

The document states that the Alere™ i Strep A 2 performance was evaluated "in comparison to bacterial culture." Bacterial culture is typically performed in a laboratory by trained microbiologists using established protocols. The document does not specify the number of experts, nor their specific qualifications (e.g., years of experience), but implies standard laboratory practices for culture results.
For discrepancies, a "laboratory developed real-time PCR assay" was used for confirmation. This also implies expert analysis within a laboratory setting, but specific expert details are not provided.

4. Adjudication Method for the Test Set

The primary ground truth for the clinical study was bacterial culture. In cases of discordance between Alere™ i Strep A 2 and bacterial culture, a "laboratory developed real-time PCR assay" was used for further investigation:
- 38 of 52 samples positive by Alere™ i Strep A 2 and negative by bacterial culture were positive by PCR.
- 1 of 3 samples negative by Alere™ i Strep A 2 and positive by bacterial culture was negative by PCR.
This suggests an implicit adjudication based on a tertiary, highly sensitive method (PCR) for resolving some discrepancies.

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 conducted. This device is an in-vitro diagnostic (IVD) molecular test, not an imaging or diagnostic assistant used by human readers in the traditional sense. The output is an automated positive/negative result.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, the clinical performance study directly reflects the standalone performance of the device (Alere™ i Strep A 2) without human interpretation affecting the result. The device is "instrument-based" and provides "automated" results. The operator's role is to perform the assay steps, but the diagnostic determination is made by the instrument/algorithm.

7. The Type of Ground Truth Used

The primary ground truth used for the clinical performance study was bacterial culture of throat swab specimens.
For discordant results, a laboratory-developed real-time PCR assay was used as a confirmatory method.

8. The Sample Size for the Training Set

The document does not provide information regarding a specific training set size. For IVD devices, especially molecular diagnostic kits, the "training" (development and optimization) process typically involves internal analytical studies rather than a distinct, prospectively collected "training set" of clinical samples with established ground truth in the same way an AI/ML algorithm might. Clinical studies are primarily for validation.

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

As a molecular diagnostic test, the "ground truth" for its development (analogous to a training set for AI) would primarily rely on well-characterized clinical samples and reference strains with known Streptococcus pyogenes status confirmed by methods like culture and sequencing during the assay development and optimization phases. However, the document does not detail this. The provided clinical study serves as the primary validation of the device against bacterial culture as the ground truth.

Summary

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May 2, 2018

Alere Scarborough, Inc. Danielle Briggeman Regulatory Affairs Specialist 10 Southgate Road Scarborough, Maine 04074

Re: K173653

Trade/Device Name: Alere i Strep A 2. Alere i instrument. Alere i Strep A 2 Control Swab Kit Regulation Number: 21 CFR 866.2680 Regulation Name: Streptococcus spp. nucleic acid-based assay Regulatory Class: Class II Product Code: PGX, OOI Dated: November 21, 2017 Received: November 28, 2017

Dear Danielle Briggeman:

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 Part 801 and Part 809); medical device 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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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.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Ribhi Shawar -S For

Uwe Scherf, 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) K173653

Device Name Alere i Strep A 2

Indications for Use (Describe)

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: K173653

SUBMITTER

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

PRIMARY CONTACT PERSON

Danielle Briggeman (207) 730-5750, ext 65925 (Office) (207) 730-5767 (FAX) Danielle.briggeman@alere.com (email)

SECONDARY CONTACT PERSON

Angela Drysdale (207) 415-1393 (Office) (207) 730-5767 (FAX) angela.drysdale@alere.com (email)

DATE PREPARED

May 1, 2018

TRADE NAME

Alere™ i Strep A 2 Alere™ i Instrument Alere™ i Strep A 2 Control Swab Kit

COMMON NAME

Alere™ i Strep 2, Alere™ i

CLASSIFICATION NAME

21 CFR 866.2680 – Streptococcus spp. Nucleic Acid-Based Assay

CLASSIFICATION Class II

PRODUCT CODES PGX, 00I

PANEL Microbiology (83)

PREDICATE DEVICE Alere i Strep A, K141757

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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 2 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 Streptococus 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 Strep bacterial infections.

TECHNOLOGICAL CHARACTERISTICS

Alere™ i Strep A 2 and the predicate device, Alere™ i Strep A, 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 Streptococcus pyogenes, Group A Strep nucleic acid.

DEVICE COMPARISON

Parameter	Alere™ i Strep A 2	Alere ™ i Strep A (K141757)
FDA Product Code	PGX, OOI	Same
Assay Target	Streptococcus pyogenes (Group A)	Same
Intended Use	Alere™ i Strep A 2 is a rapid,instrument-based, molecular in vitrodiagnostic test utilizing isothermalnucleic acid amplification technologyfor the qualitative detection ofStreptococcus pyogenes , Group AStreptococcus bacterial nucleic acid inthroat swab specimens obtained from	Alere i Strep A is a rapid, instrument-based,molecular in vitro diagnostic test utilizingisothermal nucleic acid amplificationtechnology for the qualitative detection ofStreptococcus pyogenes , Group A Streptococcusbacterial nucleic acid in throat swab specimensobtained from patients with signs andsymptoms of pharyngitis. It is intended to aidin the rapid diagnosis of Group A Streptococcus

Alere™ i Strep A 2 was compared to the legally marketed predicate device, the Alere™ i Strep A assay.

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Parameter	Alere™ i Strep A 2	Alere ™ i Strep A (K141757)
Intended Environment forUse	patients with signs and symptoms ofpharyngitis. It is intended to aid in therapid diagnosis of Group AStreptococcus bacterial infections.	bacterial infections. All negative test resultsshould be confirmed by bacterial culturebecause negative results do not precludeinfection with Group A Streptococcus andshould not be used as the sole basis fortreatment.
Intended Environment forUse	Professional use, in a medicallaboratory or point-of-care	Same
Instrumentation	Alere™ i Instrument	Same
Self-Contained System	Integrated PC, Software and TouchScreen Display	Same
Semi-Automated Assay	Sample preparation, amplification,detection and result interpretation areautomated; sample transfer isperformed manually	Same
Assay Information
Sample Type	Throat Swab	Same
Strep A Target	Streptococcus pyogenes	Same
Technology	Isothermal nucleic acid amplificationfor detecting the presence/absence ofbacterial DNA in clinical specimens	Same
Internal Control	Yes	Same
Result Interpretation	Automated	Same
Assay Result	Qualitative	Same
Time to Result	< 6 minutes	< 8 minutes

PERFORMANCE SUMMARY

CLINICAL STUDY

The clinical performance of Alere™ i Strep A 2 was established in a multi-center, prospective clinical study conducted at nine (9) US trial sites in 2017.

A total of 981 evaluable throat swab specimens, collected from patients of all ages presenting with symptoms of pharyngitis, were evaluated with Alere™ i Strep A 2, in comparison to bacterial culture.

The study population included 582 (59.3%) female patients and 399 (40.7%) male patients. No performance differences were noted based on age.

In this study, two (2) throat swabs were collected from each of 981 evaluable patients. One throat swab from each patient was tested with Alere™ i Strep A 2. The other throat swab was sent to a central laboratory for bacterial culture.

Alere™ i Strep A 2 performance, including 95% confidence intervals, versus bacterial culture is provided below.

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Alere™ i Strep A 2 Performance vs. Culture (All Age Groups Combined)

	Culture +	Culture -
Alere™ i +	195	52a	247
Alere™ i -	3b	731	734
	198	783	981

Sensitivity: 195/198 = 98.5% (95% CI = 95.6%, 99.5%) Specificity: 731/783 = 93.4% (95% CI = 91.4%, 94.9%) Positive Predictive Value: 195/247 = 78.9% (95% CI = 74.3%, 83.6%) Negative Predictive Value: 731/734 = 99.6 (95% CI = 98.3%, 99.9%) Prevalence: 198/981 =20.2% (95% CI = 17.8%, 22.8%)

a Of the 52 samples positive by Alere™ i Strep A 2 and negative by bacterial culture, 38 were also positive for Group A Strep by a laboratory developed real-time PCR assay and

b of the 3 samples negative by Alere™ i Strep A 2 and positive by bacterial culture, 1 sample was 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 0.9% (9/985) (95% Cl: 0.5%, 1.7%). After repeat testing per the product instructions, the invalid rate was 0.4% (4/985) (95% CI: 0.2%, 1.0%).

ANALYTICAL STUDIES

ANALYTICAL SENSITIVITY

Alere™ i Strep A 2 limit of detection (LOD or C s), defined as the concentration of Group A Strep that produces positive Alere™ i Strep A 2 results approximately 95% of the time, was identified by evaluating different concentrations of Group A Strep in Alere™ i Strep A 2. The concentrations identified as the LOD (or Cs5) level for each strain tested are listed below.

Group A Strep Strain	Concentration(cells/mL of Elution Buffer) 1	% Detected
ATCC 12344	147	100%
ATCC 19615	25	95%

1 As determined by correlation of optical density of cell stocks with microscopy chamber counts

REACTIVITY TESTING

The following Group A Strep strains were tested and produced positive reactions at or near the stated assay limit of detection of the Alere™ i Strep A 2 test: ATCC12384, ATCC12202, ATCC12203, ATCC12204, ATCC12365, ATCC14289, ATCC49399, ATCC51339, ATCC700294, ATCC12357, ATCC12385 Loomis, ATCC 12385 Type 4, and Z018.

ANALYTICAL SPECIFICITY (CROSS-REACTIVITY)

To determine the analytical specificity of Alere™ i Strep A 2, thirty-four (34) commensal and pathogenic microorganisms (33 bacteria and 1 yeast) that may be present in the throat were tested. All of the following microorganisms and yeast produced negative when tested at a minimum concentration of 2.00 x 106 cells/mL of elution buffer.

Bacteria Arcanobacterium haemolyticum

Yeast Candida albicans

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Bacillus cereus Bordetella pertussis Burkholderia cepacia Campylobacter rectus Corynebacterium diphtheriae Enterococcus faecalis Escherichia coli Fusobacterium necrophorum Haemophilus influenzae Klebsiella pneumoniae Lactobacillus acidophilus Moraxella catarrhalis Neisseria gonorrhoeae Peptostreptococcaceae Prevotella oralis Pseudomonas aeruginosa Staphylococcus aureus Staphylococcus epidermidis Streptococcus agalactiae Streptococcus anginosus Streptococcus canis Streptococcus constellatus subsp. pharyngis Streptococcus dysgalactiae subsp equisimilis Streptococcus gallolyticus Streptococcus intermedius Streptococcus mitis Streptococcus mutans Streptococcus pneumoniae Streptococcus salivarius Streptococcus sanguinis Treponema denticola Veillonella parvula

In addition, in silico analysis was performed to determine whether there is any significant homology between Alere™ i Strep A 2 target nucleic acid sequence and the genomes of the following upper respiratory tract microorganism. None of the organisms maintained genomic sequence that was significantly similar to the Alere™ i Strep A 2 target sequences.

Bacteria

Candida spp. Enterococcus spp. Klebsiella spp. Lactococcus lactis Legionella spp. Mycoplasma pneumoniae Pseudomonas spp. Saccharomyces cerevisiae Stenotrophomonas maltophilia

Viruses

Adenovirus Type 1 Adenovirus Type 7 Human influenza virus A Human influenza virus B Human parainfluenza Human metapneumovirus Respiratory syncytial virus Type B Rhinovirus

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 2 at the concentrations listed below and were found not to affect test performance.

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Substance	Concentration
Whole Blood	5.0% (v/v)
Mucin	1.0% (w/v) 1
Human Saliva	5.0% (v/v) ²
Ibuprophen	20 mg/mL
Acetaminophen	60.4 mg/mL
Acetylsalicylic acid	0.65 mg/mL
Albuterol	0.40 mg/mL
Diphenhydramine HCL	1.0 mg/mL
Cepacol® Sore Throat Lozenges	20% (w/v)
Sucrets® Sore Throat & Cough	20% (w/v)
Halls Plus®	20% (w/v)
ACT® Total Care	20% (v/v)
Cepacol® Mouthwash	20% (v/v)
Listerine® Antiseptic Mouthwash	10% (v/v) 3
Crest® Complete Multi-Benefit Whitening + Deep Clean Toothpaste	20% (w/v)
Zicam® Oral Mist	20% (v/v)
Chloraseptic® Max Sore Throat Relief + Coating Action	20% (v/v)
Contact Cold & Flu Tablets	20% (w/v)
Robitussin® Maximum Strength Nighttime Cough DM	20% (v/v)
Tylenol® Cold Multi-Symptom Liquid	20% (v/v)
Children's Dimetapp® Cough & Cold	20% (v/v)

1 1/3 replicates at 2% w/v mucin produced a false-negative result

² 1/3 replicates at 10% v/v saliva produced a false-negative result

3 1/3 replicates at 20% v/v Listerine Antiseptic Mouthwash produced a false-positive result

REPRODUCIBILITY

A reproducibility study of Alere™ i Strep A 2 was conducted by operators from 3 sites using panels of blind coded specimens containing negative, low positive (~2X the limit of detection), and moderate positive (~3X 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 Group A Strep moderate positive and low positive samples were both 100% (90/90). All of the negative samples (90) generated negative test results. There were no significant differences within run (replicates tested by one operator), between run (five different days), between sites (three sites), or between operators (nine operators).

CONCLUSION

The submitted information in this premarket notification is complete and supports a substantial equivalence decision.

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.