T2Candida 1.1 Panel

K173536 · T2biosystems, Inc. · PII · Dec 12, 2017 · Microbiology

Device Facts

• Record ID: K173536
• Device Name: T2Candida 1.1 Panel
• Applicant: T2biosystems, Inc.
• Product Code: PII · Microbiology
• Decision Date: Dec 12, 2017
• Decision: SESE
• Submission Type: Special
• Regulation: 21 CFR 866.3960
• Device Class: Class 2

Indications for Use

The T2Candida 1.1 Panel run on the T2Dx® Instrument is a qualitative T2 Magnetic Resonance (T2MR®) assay for the direct detection of Candida species in EDTA human whole blood specimens from patients with symptoms of, or medical conditions predisposing the patient to, invasive fungal infections. The T2Candida Panel identifies five species of Candida and categorizes them into the following three groups: 1. Candida albicans and/or Candida tropicalis, 2. Candida parapsilosis 3. Candida qlabrata and/or Candida krusei The T2Candida 1.1 Panel does not distinguish between C. albicans and C. tropicalis. The T2Candida 1.1 Panel does not distinguish between C. glabrata and C. krusei. The T2Candida Panel is indicated for the presumptive diagnosis of candidemia. The T2Candida Panel is performed independent of blood culture. Concomitant blood cultures are necessary to recover organisms for susceptibility testing or further identification. The T2Candida positive (T2Candida QCheck) and negative External Controls (T2Dx QCheck) are intended to be used as quality control samples with the T2Candida 1.1 Panel when run on the T2Dx Instrument. These controls are not intended for use with other assays or systems.

Device Story

T2Candida 1.1 Panel is a qualitative in vitro diagnostic assay for direct detection of Candida species in whole blood; utilizes T2 Magnetic Resonance (T2MR) technology. Device processes K2EDTA-treated human whole blood samples on the T2Dx Instrument, a bench-top, automated sample-to-result system. Workflow includes sample concentration and DNA amplification to detect species-specific amplicons; limit of detection as low as 1 CFU/mL; total turnaround time approximately 3.5 hours. Internal control monitors test performance. Designed for use in clinical settings; operated by laboratory personnel. Output provides presumptive identification of Candida species groups; assists clinicians in rapid diagnosis of candidemia, enabling earlier targeted therapy. Concomitant blood cultures required for susceptibility testing. Design modification involved removing bleach-containing decontamination tubes from the cartridge and updating software to remove associated transfer steps; improves product shelf-life stability without impacting assay performance or fundamental technology.

Clinical Evidence

Bench testing only. Specificity studies compared T2Candida 1.1 Panel performance against the original T2Candida Panel (DEN140019) using human whole blood spiked with Candida species. Results demonstrated statistically equivalent specificity (Overall 99.5% vs 99.7%). Stability studies confirmed that removing bleach steps mitigated stability issues, allowing for an 8-month shelf-life.

Technological Characteristics

T2 Magnetic Resonance (T2MR) technology; qualitative nucleic acid-based detection. Bench-top, automated sample-to-result system (T2Dx Instrument). K2EDTA whole blood input. Workflow: sample concentration, DNA amplification, T2MR detection. Internal control included. Software-controlled automated processing. No bleach-based decontamination steps.

Indications for Use

Indicated for presumptive diagnosis of candidemia in patients with symptoms or predisposing conditions for invasive fungal infections. Detects Candida albicans, C. tropicalis, C. parapsilosis, C. glabrata, and C. krusei in K2EDTA whole blood.

Regulatory Classification

Identification

A nucleic acid-based device for the amplification, detection, and identification of microbial pathogens directly from whole blood specimens is a qualitative in vitro device intended for the amplification, detection, and identification of microbial-associated nucleic acid sequences from patients with suspected bloodstream infections. This device is intended to aid in the diagnosis of bloodstream infection when used in conjunction with clinical signs and symptoms and other laboratory findings.

Special Controls

A nucleic acid-based device for the amplification, detection and identification of microbial pathogens directly from whole blood specimens must comply with the following special controls:

*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, carryover, 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) The device labeling must include limitations regarding the need for culture confirmation of negative specimens, as appropriate. (6) 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. (7) Premarket notification submissions must include details on an end user device training program that will be offered while marketing the device, as appropriate. (8) As part of the risk management activities performed under 21 CFR 820.10(c) design and development, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument.

Predicate Devices

• T2Candida Panel (DEN140019)

Submission Summary (Full Text)

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SPECIAL 510(k): Device Modification OIR Decision Summary

To: THE FILE

RE: DOCUMENT NUMBER K173536

This 510(k) submission contains information/data on modifications made to the SUBMITTER'S own Class II, Class III or Class I devices requiring 510(k). The following items are present and acceptable (delete/add items as necessary):

1. The name and 510(k) number of the SUBMITTER'S previously cleared device. (For a preamendments device, a statement to this effect has been provided.)

Trade Name: T2Candida Panel and T2Dx Instrument
DeNovo: DEN140019

2. Submitter's statement that the INDICATION/INTENDED USE of the modified device as described in its labeling HAS NOT CHANGED along with the proposed labeling which includes instructions for use, package labeling, and, if available, advertisements or promotional materials (labeling changes are permitted as long as they do not affect the intended use).

Submitter states in the submission that the intended use of the modified device has not changed from its predicate.

3. A description of the device MODIFICATION(S), including clearly labeled diagrams, engineering drawings, photographs, user's and/or service manuals in sufficient detail to demonstrate that the FUNDAMENTAL SCIENTIFIC TECHNOLOGY of the modified device has not changed. The modifications include the following

- Decreased cartridge stability (shelf life) was linked to the presence of two sealed post-testing decontamination bleach tubes. These bleach tubes have been removed from the T2Candida 1.1 Panel,
- Modification of the T2Candida software to remove the bleach transfer steps from the T2Dx workflow,
- Relabeling of the T2Candida External Positive and Negative Controls

4. Comparison Information (similarities and differences) to applicant's legally marketed predicate device including, labeling, intended use, physical characteristics, and software as shown in the table below.

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| Similarities | | |
| --- | --- | --- |
| Item | Proposed Device: T2Candida 1.1 Panel (K173536) | Predicate Device: T2Candida Panel (DEN140019) |
| Intended Use | T2Candida 1.1 Panel and T2Dx Instrument is a qualitative T2 Magnetic Resonance (T2MR) assay for the direct detection of Candida species in K2EDTA human whole blood specimens from patients with symptoms of, or medical conditions predisposing the patient to, invasive fungal infections. The T2Candida1.1 Panel identifies five species of Candida and categorizes them into the following three species groups:
1. Candida albicans and/or Candida tropicalis
2. Candida parapsilosis
3. Candida glabrata and/or Candida krusei

The T2Candida 1.1 Panel is indicated for the presumptive diagnosis of candidemia. The T2Candida 1.1 Panel is performed independent of blood culture. Concomitant blood cultures are necessary to recover organisms for susceptibility testing or further identification. | T2Candida Panel and T2Dx Instrument is a qualitative T2 Magnetic Resonance (T2MR) assay for the direct detection of Candida species in K2EDTA human whole blood specimens from patients with symptoms of, or medical conditions predisposing the patient to, invasive fungal infections. The T2Candida Panel identifies five species of Candida and categorizes them into the following three species groups:
1. Candida albicans and/or Candida tropicalis
2. Candida parapsilosis
3. Candida glabrata and/or Candida krusei

The T2Candida Panel is indicated for the presumptive diagnosis of candidemia. The T2Candida Panel is performed independent of blood culture. Concomitant blood cultures are necessary to recover organisms for susceptibility testing or further identification. |
| Indication for Use | The T2Candida 1.1 Panel is indicated for the presumptive diagnosis of candidemia. The T2Candida 1.1 Panel is performed independent of blood culture. Concomitant blood cultures are necessary to recover organisms for susceptibility testing or further identification. | The T2Candida Panel is indicated for the presumptive diagnosis of candidemia. The T2Candida Panel is performed independent of blood culture. Concomitant blood cultures are necessary to recover organisms for susceptibility testing or further identification. |
| Sample Type | 4 ml whole blood collected in a blood collection tube with EDTA coagulant | Same |
| Test Platform | T2Dx | Same |
| Test Principle | PCR amplification followed by T2 patented medical resonance detection | Same |
| Throughput | Single cartridge test with random access with 7 draws on T2Dx | Same |

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| Differences | | |
| --- | --- | --- |
| Item | Proposed Device: T2Candida 1.1 Panel (K173536) | Predicate Device: T2Candida Panel (DEN140019) |
| Device name | T2Candida Panel 1.1 | T2Candida Panel |
| Test Cartridge Format | T2Candida 1.1 Panel Test Cartridge and disposables.
No Bleach Tube – T2Candida 1.1 Panel Cartridge does not contain the two (2) bleach tubes or need for bleach transfer steps | T2Candida Panel Test Cartridge and disposables.
Bleach Tubes included as part of cartridge and instructions enclosed |
| Cartridge stability (shelf life) | 8 months | 7 months |
| External Controls | The T2Candida positive and negative External Controls (T2Candida QCheck Positive and T2Dx QCheck Negative) are intended to be used as quality control samples with the T2Candida 1.1 Panel when run on the T2Dx Instrument. These controls are not intended for use with other assays or systems. | The T2Candida positive and negative External Controls are intended to be used as quality control samples with the T2Candida Panel when run on the T2Dx Instrument. These controls are not intended for use with other assays or systems. |
| Software | Software v. 1.5.2.XXXX (finalized build number pending) is the upgrade to SW v.1.0.0.1031, eliminating workflow software commands for the final bleach transfer steps, prior to kit drawer ejection and disposal of assembled kit after test is completed. | Software v. 1.0.0.1031 includes bleach transfer steps performed prior to kit drawer ejection and disposal of assembled kit after test is completed. |

The indications for use provided below are identical for both devices, except for renaming of the panel from T2Candida to T2Candida 1.1 and rebranding of the External Posive and Negative Controls.

## Indications for use

The T2Candida 1.1 Panel run on the T2Dx Instrument is a qualitative T2 Magnetic Resonance (T2MR) assay for the direct detection of Candida species in EDTA human whole blood specimens from patients with symptoms of, or medical conditions predisposing the patient to, invasive fungal infections. The T2Candida Panel identifies five species of Candida and categorizes them into the following three groups:

1. Candida albicans and/or Candida tropicalis,
2. Candida parapsilosis
3. Candida glabrata and/or Candida krusei

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The T2Candida 1.1 Panel does not distinguish between C. albicans and C. tropicalis. The T2Candida 1.1 Panel does not distinguish between C. glabrata and C. krusei. The T2Candida Panel is indicated for the presumptive diagnosis of candidemia. The T2Candida panel is performed independent of blood culture. Concomitant blood cultures are necessary to recover organisms for susceptibility testing or further identification.

The T2Candida positive (T2Candida QCheck) and negative External Controls (T2Dx QCheck) are intended to be used as quality control samples with the T2Candida 1.1 Panel when run on the T2Dx Instrument. These controls are not intended for use with other assays or systems.

5. A Design Control Activities Summary which includes:

a) Identification of Risk Analysis method(s) used to assess the impact of the modification on the device and its components, and the results of the analysis.

A formal risk assessment was performed for the elimination of bleach tubes from the cartridge and impact on the T2Candida 1.1 Panel. The risk assessment performed utilized the T2Candida and T2Dx risk and hazard documentation including failure modes effects analyses (FMEAs), risk management reports and hazard assessment in order to review all content associated with the removal of the bleach tubes and cleanup step of the T2Dx system workflow. The risk analysis identified the following risks.

1. Potential increase in false positive results due to contamination carryover of Candida spp. Amplicon external to the instrument from operator handling of consumables (touch-and-go contamination).
2. Potential for incorrect operation of the instrument due to software changes to modify the T2Candida on-instrument assay workflow.

b) Based on the Risk Analysis, an identification of the verification and/or validation activities required, including methods or tests used and acceptance criteria to be applied.

The studies below were performed to demonstrate risk mitigation.

Carryover and Cross-contamination study

A carryover and cross-contamination study was conducted. Human whole blood pooled from healthy donors was triple-spiked with either 100 CFU/mL or 1000 CFU/mL of C.albicans, C. parapsilosis and C.glabrata (APG) or C. tropicalis, C. parapsilosis and C. krusei (TPK). There were 49 APG (37 samples at 100 CFU/mL and 12 samples at 1000 CFU/mL) and 48 TPK (36 samples at 100 CFU/mL and 12 samples at 1000 CFU/mL) included in the study. One-hundred twenty nine (129) negative human whole blood samples were tested alongside the spiked, positive samples. Samples were loaded such that the Negative Samples and Positive APG or TPK samples were positioned in adjacent, alternating drawers. Two T2Candida 1.1 Panel cartridge lots and two reagent tray packs were and two T2Dx instruments were used in this study. Results were compared with the original data submitted to FDA (DEN140019) (Table 1). For all channels specificity was found to be $\geq 99\%$. These results support the risk assessment that removal of the bleach tubes results in similar assay specificity as reported for the original cleared test.

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Table 1. Results of Carry-Over and Cross-Contamination Studies for the Modified and Predicate Devices

| Channel | T2Candida Panel %Specificity (95% CI) | T2Candida 1.1 Panel %Specificity (95% CI) |
| --- | --- | --- |
| A/T | 216/217 (99.5; 97.4-99.9) | 128/128 (100; 97.1-100) |
| P | 217/217 (100; 98.3-100) | 127/128 (99.2; 95.7-99.9) |
| K/G | 216/217 (99.5; 97.4-99.9) | 127/128 (99.2; 95.7-99.9) |
| Overall | 649/651 (99.7; 98.9-99.9) | 382/384 (99.5; 98.1-99.9) |

# Cartridge Stability study

The T2Candida Panel cartridge was originally approved for use up to 8 months. However, decreased cartridge stability was identified by the sponsor and was attributed to corrosion of in-cartridge reagents, including those involved in PCR amplification. Thus, it was determined that bleach tubes, which only serve as a precautionary element of post-testing decontamination, should be removed from the cartridge. To assess the stability of the cartridge without bleach tubes, a real-time cartridge stability study was performed that measured T2MR signal at baseline $(T = 0)$ , 1, 2, 3, 4, 6, 7, 8, and 9 months post-initiation. The study is also planned to continue to assess stability at 13 months post-initiation. Three (3) T2Candida 1.1 cartridge validation lots were tested during the course of the study, with two (2) lots stored at room temperature $(15^{\circ}\mathrm{C} - 30^{\circ}\mathrm{C})$ and one lot stored in a controlled incubator at $30^{\circ}\mathrm{C}$ . For each cartridge lot and time point eight (8) QCheck APG Positive External Controls and eight (8) T2Dx QCheck Negative External Control were evaluated. Cartridges were tested on multiple T2Dx instruments throughout the study. Stability acceptance criteria were as follows: For each time point tested for each lot, the A/T, P, and K/G channels of the T2Candida QCheck APG Positive control must be i) valid results with all channels POSITIVE and; ii) within a $45\%$ negative drift in the difference of mean T2MR values at $T = 0$ baseline. Similarly, all channels must be NEGATIVE (except for the Interal Control (IC)) for the T2Dx QCheck Negative control. Further, the IC channel of the T2Dx QCheck Negatives must also be within a $45\%$ negative drift in the difference of mean T2MR values at $T = 0$ baseline. The A/T, P, and K/G baseline levels in the T2Dx QCheck Negatives were also verified to be within a $45\%$ positive drift in the difference of mean T2MR values determined at $T = 0$ . At present, all stability time points for the 3 cartridge lots have passed all acceptance criteria out to 9 months, establishing stability for 8 months (Table 2). These results are acceptable.

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Table 2. Summary of Cartridge Stability Testing to Date

| Time point | Negative Sample Equivalence Test | | | Positive Sample Equivalence Test | | |
| --- | --- | --- | --- | --- | --- | --- |
| Cartridge Stability Lot | Lot 1 WO-05642 | Lot 2 WO-05822 | Lot 3 WO-05920 | Lot 1 WO-05642 | Lot 2 WO-05822 | Lot 3 WO-05920 |
| One Months (T1) | Pass | Pass | Pass | Pass | Pass | Pass |
| Two Months (T2) | Pass | Pass | Pass | Pass | Pass | Pass |
| Three Months (T3) | Pass | Pass | Pass | Pass | Pass | Pass |
| Four Months (T4) | Pass | Pass | Pass | Pass | Pass | Pass |
| Six Months (T6) | Pass | Pass | Pass | Pass | Pass | Pass |
| Seven Months (T7) | Pass | Pass | Pass | Pass | Pass | Pass |
| Eight Months (T8) | Pass | Pass | Pass | Pass | Pass | Pass |
| Nine Months (T9) | Pass | Pass | Pass | Pass | Pass | Pass |

# Software Modifications

Elimination of the the bleach steps required modifications to the T2Dx software v. 1.0.0.1031. The set of commands which executed the bleach transfer from the bleach tubes to all spent reaction wells in the cartridge assembly were eliminated for the T2Candida 1.1 Panel. The removed software commands do not interact with other steps in the workflow and are executed after results are reported; therefore, results reporting are not affected. All modifications are classified as low risk. These changes are acceptable.

Additionally, software updates have been made to the T2Dx platform that enhance the reliability of the platform and to integrate T2Bacteria Panel Assay Definition Files into the overall menu. Included in these changes are modifications to results reporting. The original T2Candida Panel did not distinguish a potential assay error from an instrument error – all errors that led to no results reported were classified as “Invalid”. In the updated version (v. 1.5.2.XXX), potential assay errors due to low IC signal are returned as “Invalid” while other potential failures are reported as “Results Not Reported”. These changes are acceptable.

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c) Declaration of Conformity to Design Controls

A “Declaration of Conformity” statement was submitted the T2 Biosystems, Inc. The statements are written below. Statement i and ii were signed by the Senior Director of Quality Management. The statements indicate that:

i. “To the best of my knowledge, the verification activities, as required by the risk analysis, for the modification were performed by the designated individual(s) and the results demonstrated that the predetermined acceptance criteria were met.”
ii. The manufacturing facility, T2 Biosystems, Inc. is in conformance with the design control requirements as specified in 21 CFR 820.30 and the records are available for review.”

The labeling for this modified subject device has been reviewed to verify that the indication/intended use for the device is unaffected by the modification. In addition, the submitter’s description of the particular modification(s) and the comparative information between the modified and unmodified devices demonstrate that the fundamental scientific technology has not changed. The submitter has provided the design control information as specified in The New 510(k) Paradigm and on this basis, I recommend the device be determined substantially equivalent to the previously cleared (or their preamendment) device.

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