RefleXion Medical Radiotherapy System (RMRS)

• K Number: DEN220014
• Device Name: RefleXion Medical Radiotherapy System (RMRS)
• Manufacturer: RefleXion Medical Inc
• Date Cleared: 2023-02-01 ( 343 days)
• Product Code: QVA OVA
• Regulation Number: 892.5060

Intended Use

The RefleXion Medical Radiotherapy System (RMRS) is indicated for treatment planning and precise delivery of image-guided radiation therapy, stereotactic radiotherapy, or stereotactic radiosurgery for tumors or other targeted tissues anywhere in the body when radiation treatment is indicated. while minimizing the delivery of radiation to vital healthy tissue. The megavoltage X-ray radiation is delivered in a rotational, modulated, image-guided format in accordance with the physician approved plan. The RefleXion Medical Radiotherapy System is also indicated for FDG-guided treatment which includes modeling, planning and precise delivery of FDG-guided radiation therapy, a type of Biology-guided Radiotherapy (BgRT), in five or fewer fractions for adults. It is indicated for tumor volumes in lung and bone subject to potential motion and positional uncertainty that have each been assessed with on-board PET/CT prior to delivery for adequate localization, sufficient FDG metabolic activity, local contrast and consistent biodistribution to meet the RMRS requirements, while minimizing the delivery of radiation to vital healthy tissue. BgRT involves the detection of signals from F18 during active beam delivery as a guide to deliver megavoltage X-ray radiotherapy in a rotational, modulated format in accordance with a physician approved treatment plan. For complete fludeoxyglucose F18 prescribing information, refer both to the current medical imaging agent labeling and to this device labeling under "FDG Medical Imaging Agent Information".

Device Description

The RMRS is a linear accelerator capable of delivering intensity-modulated radiation therapy, stereotactic body radiation therapy, stereotactic radiotherapy, stereotactic radiosurgery, and biology-guided radiotherapy (BgRT). The RMRS is comprised of six major subsystems as shown in Figure 1. The major subsystems of the RefleXion Medical Radiotherapy System are: 1) Compact linear accelerator, 2) primary collimation, 4) PET scanner, 5) kVCT, and 6) MV x-ray detectors. The linear accelerator portion of the device was previously cleared under a 510(k) premarket notification (K190978). The subject device in K190978 included the PET hardware, but the PET hardware and associated software was inactive and outside the scope of K190978. The subject of the current submission is the addition of the BgRT functionality and the activation of the PET hardware. Biology-guided Radiation Therapy BgRT is a type of volumetric modulated arc therapy that allows radiation dose delivery in a slice-by-slice fashion using a multi-pass couch motion based on the collection and processing of PET data from the radiotracer fludeoxyglucose F18 (FDG). BgRT also allows the dose delivery to be adjusted in real-time to account for target motion in the lung and bone. The PET system is comprised of two PET detector arcs mounted on the ring gantry that rotate with the system to generate complete tomographic samples of radiotracer distribution required for the BgRT algorithm. Rapidly acquired "limited time sampled" (LTS) PET imaging data are used to form accumulated lines of response (projection data). These data are then used to guide the beam using the mapping calculated during BgRT planning, maintaining the ability to track the target in real-time as it moves within a pre-defined volume called the biology-tracking zone (BTZ).

Predicate Devices

K190978

Reference Devices

K190978

AI/ML (Artificial Intelligence / Machine Learning)

Yes
The device description explicitly mentions a "BgRT algorithm" that processes PET data to guide the beam and adjust dose delivery in real-time to account for target motion. While the terms AI or ML are not used, the description of a real-time adaptive algorithm based on complex data processing strongly suggests the use of advanced computational techniques that fall under the umbrella of AI/ML in medical devices. The ability to "track the target in real-time as it moves" and adjust dose delivery based on "rapidly acquired 'limited time sampled' (LTS) PET imaging data" points towards a system that learns or adapts based on incoming data, a core characteristic of ML.

Therapeutic

Yes
The device delivers radiation therapy for treating tumors and other targeted tissues, fulfilling the definition of a therapeutic device.

Diagnostic

No

The device is a radiotherapy system that delivers radiation treatment, which is a therapeutic function. While it uses imaging (PET/CT) for planning and guiding the treatment, its primary indication is for treatment delivery rather than diagnosing a condition. The imaging components are used to guide the therapeutic intervention.

SaMD (Software as a Medical Device)

No

The device description explicitly states that the RMRS is comprised of six major subsystems, including a linear accelerator, primary collimation, PET scanner, kVCT, and MV x-ray detectors. These are all hardware components. The submission is for the addition of BgRT functionality and activation of the PET hardware, further indicating the presence of physical hardware.

IVD (In Vitro Diagnostic)

Based on the provided information, the RefleXion Medical Radiotherapy System (RMRS) is not an In Vitro Diagnostic (IVD).

Here's why:

• Intended Use: The primary intended use of the RMRS is for treatment planning and precise delivery of radiation therapy for tumors and other targeted tissues. While it uses imaging modalities (PET/CT, kVCT, PET) and a radiotracer (FDG) to guide this treatment, its function is to deliver radiation, not to perform diagnostic testing on samples taken from the human body.
• Device Description: The device is described as a linear accelerator with integrated imaging components (PET scanner, kVCT, MV x-ray detectors). Its core function is the generation and delivery of megavoltage X-ray radiation.
• IVD Definition: An In Vitro Diagnostic (IVD) device is defined as a medical device intended for use in vitro for the examination of specimens derived from the human body solely or principally for the purpose of providing information concerning a physiological state, state of health, disease or congenital abnormality. The RMRS does not examine specimens derived from the human body in this manner. It uses imaging data from within the body to guide the delivery of radiation.

While the RMRS utilizes PET imaging and the radiotracer FDG, which are components often associated with diagnostic procedures, the device's overall purpose and mechanism of action are therapeutic (delivering radiation) rather than diagnostic (analyzing samples for diagnostic information). The PET data is used to guide the delivery of the therapy, not to diagnose a condition from a sample.

PCCP (Predetermined Change Control Plan) Authorized

No
The letter mentions "Control Plan Authorized (PCCP)" and has a "Yes" next to it, but the subsequent text only lists risks and special controls. It does not explicitly state that the FDA has reviewed and approved or cleared a PCCP for this specific device, as required by the Key Decision Rules.

Overview

Intended Use / Indications for Use

The RefleXion Medical Radiotherapy System (RMRS) is indicated for treatment planning and precise delivery of image-guided radiation therapy, stereotactic radiotherapy, or stereotactic radiosurgery for tumors or other targeted tissues anywhere in the body when radiation treatment is indicated, while minimizing the delivery of radiation to vital healthy tissue. The megavoltage X-ray radiation is delivered in a rotational, modulated, image-guided format in accordance with the physician approved plan.

The RefleXion Medical Radiotherapy System is also indicated for FDG-guided treatment which includes modeling, planning and precise delivery of FDG-guided radiation therapy, a type of Biology-guided Radiotherapy (BgRT), in five or fewer fractions for adults. It is indicated for tumor volumes in lung and bone subject to potential motion and positional uncertainty that have each been assessed with on-board PET/CT prior to delivery for adequate localization, sufficient FDG metabolic activity, local contrast and consistent biodistribution to meet the RMRS requirements, while minimizing the delivery of radiation to vital healthy tissue. BgRT involves the detection of signals from F18 during active beam delivery as a guide to deliver megavoltage X-ray radiotherapy in a rotational, modulated format in accordance with a physician approved treatment plan.

For complete fludeoxyglucose F18 prescribing information, refer both to the current medical imaging agent labeling and to this device labeling under "FDG Medical Imaging Agent Information".

Product codes

QVA

Device Description

The RMRS is a linear accelerator capable of delivering intensity-modulated radiation therapy, stereotactic body radiation therapy, stereotactic radiosurgery, and biology-guided radiotherapy (BgRT).

The RMRS is comprised of six major subsystems as shown in Figure 1.

Figure 1. The major subsystems of the RefleXion Medical Radiotherapy System are: 1) Compact linear accelerator, 2) primary collimation, 4) PET scanner, 5) kVCT, and 6) MV x-ray detectors.

The linear accelerator portion of the device was previously cleared under a 510(k) premarket notification (K190978). The subject device in K190978 included the PET hardware, but the PET hardware and associated software was inactive and outside the scope of K190978. The subject of the current submission is the addition of the BgRT functionality and the activation of the PET hardware.

Biology-guided Radiation Therapy

BgRT is a type of volumetric modulated arc therapy that allows radiation dose delivery in a slice-by-slice fashion using a multi-pass couch motion based on the collection and processing of PET data from the radiotracer fludeoxyglucose F18 (FDG). BgRT also allows the dose delivery to be adjusted in real-time to account for target motion in the lung and bone.

The PET system is comprised of two PET detector arcs mounted on the ring gantry that rotate with the system to generate complete tomographic samples of radiotracer distribution required for the BgRT algorithm.

Rapidly acquired "limited time sampled" (LTS) PET imaging data are used to form accumulated lines of response (projection data). These data are then used to guide the beam using the mapping calculated during BgRT planning, maintaining the ability to track the target in real-time as it moves within a pre-defined volume called the biology-tracking zone (BTZ). The BTZ is the volume within which primary dose delivery is allowed. It encompasses the motion extent (internal target volume or ITV), biology-guidance margin (BgM) and the set-up margin (SM) (Figure 2). Unlike standard radiotherapy, the planning target volume (PTV) expansion for BgRT only includes the biology-guidance margin (BgM) and not the motion extent with internal margin (IM) or the set-up margin since the delivery tracks the PTV. The clinical target volume (CTV) and the gross tumor volume (GTV) are the same between BgRT and standard RT. The treatment delivery system uses the BTZ as a limiting factor in the delivery of the prescription dose.

In order to ensure sufficient FDG signal during planning and on the day of treatment, the treatment planning software calculates two quantitative parameters from the tumor PET image to determine whether BgRT is a viable option:

• . Activity Concentration (AC) - a minimum FDG activity concentration calculated by estimating the net signal concentration from the target.
• Normalized Target Signal (NTS) Calculated by taking the Activity Concentration . (focused on the target signal) normalized by the noise in the background around the BTZ.

An AC of > 5 kBq/ml at the time of treatment planning and treatment delivery ensures sufficient counts in the LTS PET image to translate to accurate fluence (hence accurate dose). An NTS of ≥ 2.7 at the time of treatment planning and ≥ 2.0 at the time of treatment delivery ensures adequate PET tumor contrast (tumor signal to background) for the system to calculate the fluence for both the planning and treatment delivery.

Mentions image processing

Yes

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

PET, CT, kVCT

Anatomical Site

Anywhere in the body, specifically tumor volumes in lung and bone.

Indicated Patient Age Range

Adults. Clinical study population included adults 21 years or older.

Intended User / Care Setting

Not Found

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

Non-clinical/Bench Studies

The document describes performance testing conducted using phantoms.

• Sample Size: Not explicitly stated as a number of samples, but rather as test cases performed on phantoms with varying conditions.
• Data Source: In-house bench testing using anthropomorphic phantoms and the ArcCHECK Model (b)(4) phantom. Background consisted of water with FDG to simulate an FDG-active background. For motion tests, two arms were included that could be programmed with distinct motion patterns and inserts of varying shape/size (sphere, C-shape, ovoid) were injected with FDG to simulate targets or OARs.
• Annotation Protocol: Inserts were injected with FDG to simulate targets or OARs. For the OAR, a point dose measurement was made by a calibrated ion chamber, and the maximum dose was measured on radiochromic film inserted into the OAR structure. These were compared against planned doses. Gamma index was used for comparison of the plan dose to measured dose, with criteria of 3% in dose or 3mm in 3D space. Bounded DVH was also used.

Clinical Study (Cohort I & II)

The clinical study was conducted in silico, meaning it assessed effectiveness through the use of data simulated. It was a single-arm, prospective, IDE clinical trial at two sites in the U.S.

• Sample Size:
  • Cohort I: 8 patients total enrolled, 6 had evaluable images.
  • Cohort II: 9 patients total enrolled.
• Data Source:
  • Cohort I: Patient data obtained from an external system PET/CT for initial contouring. Patients underwent back-to-back PET scans on the RMRS device and a third-party diagnostic PET/CT device after a single injection of FDG.
  • Cohort II: RMRS PET collections were added to the SBRT workflow at 3 timepoints (pre-SBRT, before first and final SBRT fractions). A single comparison third-party diagnostic PET/CT image was obtained (utilizing the same FDG injection) on the day of the final fraction. PET collections consisted of short-duration (PreScan Evaluation) and long-duration (active BgRT delivery fraction) phases.
• Annotation Protocol:
  • Cohort I: Users drew contours on a simulation CT on third-party software for targets, OARs, and BTZ. Quantitative metrics were collected for each lesion to assess the performance of the RMRS PET subsystem in comparison to a third-party diagnostic PET/CT.
  • Cohort II: The long-duration PET collection data was used to determine the hardware instructions that would be transmitted to the RMRS delivery hardware based upon the algorithmic interaction between the incoming LTS images and the approved BgRT treatment plan. The study aimed to emulate and assess the entire end-to-end BgRT workflow without actually delivering radiation therapy to the patient.

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

Non-clinical/Bench Studies

• Study Type: Performance testing using phantoms.
• Sample Size: Not explicitly given as a numerical count of samples, but as various test scenarios (moving target, step shift, clinical variations, special edge cases, ON/OFF motion, multi-target).
• AUC, MRMC, standalone performance: Not directly reported in these terms. Performance was assessed via dosimetric coverage, coverage margin loss, point dose measurements, gamma index, and bounded DVHs.
• Key Results:
  • Moving target with 3-D respiratory and 3-D non-respiratory motion; organs at risk (OARs) independent motion: Both dosimetric coverage criteria as well as OAR dose criteria were met for all BgRT test cases. Under the same test circumstances, SBRT plans with an ITV approach for the target were not able to successfully meet the same criteria as the BgRT plans.
  • Target or OAR with a single step shift: Both dosimetric coverage criteria as well as OAR dose criteria were met for all BgRT test cases. Under the same test circumstances, SBRT plans with an ITV approach for the target were not able to successfully meet the same criteria as the BgRT plans.
  • Test clinical variations of targets (stationary): For all tests where the acceptance criteria required both the PET evaluation to pass and either the post-treatment dose evaluation against the plan and/or the Gamma index to pass met the dose accuracy criteria. For cases where there was a significant change in biodistribution in the target, low contrast between the target and background, or a change in the background signal, the PET evaluation did not pass, and the resulting dose accuracy showed mixed results.
  • Tests evaluating special edge cases (stationary): For cases where there was a significant change in biodistribution between planning and delivery, or a situation when an FDG-avid target moves into the BTZ, the PET evaluation did not pass.
  • BgRT ON/OFF with Motion ON/OFF:
    • BgRT ON Motion ON: The tracked dose delivery was successfully provided where the CTV was fully covered (100%) in all cases. In cases for which the PET evaluation did not pass, some degradation to margin loss was observed.
    • BgRT OFF Motion ON: In all cases dose accuracy failed the criteria. The CTV dose coverage was less than 100% and margin loss higher than 3.0mm.
    • BgRT ON Motion OFF: All test cases met the dose accuracy criteria.
    • BgRT OFF Motion OFF: All test cases met the dose accuracy criteria.
  • Multi-target testing: For all 3-target, moving tests, including with reduced target:background for the second and third targets, all dosimetric criteria (CTV dose coverage and Margin Loss) were met.
  • PET subsystem verification: All tests for spatial resolution, scatter fraction and count rate measurements, sensitivity, and image quality, as well as PET System Performance Checks, PET image reconstruction and attenuation correction passed the pre-defined acceptance criteria.
  • Subsystem integration: kVCT, MV x-ray detectors (MVD), Beamgen, Collimation, Couch, Treatment planning, Treatment delivery. Testing was performed in accordance with standards and found acceptable.

Clinical Study (in silico)

• Study Type: Single-arm, prospective, IDE clinical trial, effectiveness assessed through in silico data simulation.
• Sample Size:
  • Cohort I: 8 patients total, 6 evaluable for images.
  • Cohort II: 9 patients total.
• AUC, MRMC, standalone performance: Not reported in these terms. Performance was assessed by agreement percentages for localization decisions, concordance of "plan proceed" decisions, percentage of acceptable plans generated, and percentage of plans meeting gamma index criteria. No AUC or MRMC results provided.
• Key Results:
  • Cohort I (Primary Objective: Recommended RefleXion FDG Dose (RRFD)):
    • Primary Endpoint: All 6 evaluable cases met the Activity Concentration threshold for BgRT functionality (>= 5 kBq/ml).
  • Cohort I (Secondary Objective: BgRT PET imaging-only session performance, treatment planning, QA):
    • Endpoint 1 (Localization decision agreement): Overall % agreement = 83.3% (5/6).
    • Endpoint 2 (Concordance of positive "plan proceed" with third-party diagnostic PET/CT): Positive % agreement = 100% (6/6). Overall % agreement = 83.3%.
    • Endpoint 3 (RefleXion PET data used to generate acceptable BgRT plan): 67% (4/6).
    • Endpoint 4 (Intentional dose distribution achieved in physical phantom via gamma index): 67% (4/6); 100% (4/4) for cases with acceptable plan.
    • Safety: 62.5% (5/8) experienced Any TEAEs, with musculoskeletal and connective tissue disorders (50%) and gastrointestinal disorders (37.5%) being most common. No serious adverse events reported.
  • Cohort II (Primary Objective: Dose distribution consistency):
    • Primary Endpoint: Percent of radiotherapy fractions where the emulated BgRT dose distribution in silico was shown to be consistent with the approved BgRT treatment plan (i.e., 95% of DVH Delivered points for the BTZ and OAR fell within bounded DVH of the approved BgRT plan). All but one evaluable fraction (17/18) passed this criterion.
  • Cohort II (Secondary Objective):
    • Endpoint 1 (Concordance between physical and digital phantoms via gamma index): 100% (18/18).
    • Endpoint 2 (BgRT PET PreScan localization decision agreement): Overall % agreement = 72.2% (13/18). Positive % agreement = 80%.
    • Endpoint 3 (Concordance of positive localization decision with third-party diagnostic PET/CT): Positive % agreement = 100% (7/7). Overall % agreement = 100%.
    • Endpoint 4 (Safety of multiple FDG administrations and toxicity rates): Reported events were documented as not being related to the study device or FDG injection. None resulted in discontinuation.
    • Workflow Characterization:
      • 5a (PET imaging sessions meeting AC threshold): 100% (18/18 fractions).
      • 5b (PET imaging sessions leading to acceptable BgRT plans): 100% (9/9 cases).
      • 5c (Approved BgRT plans passing physics QA): 100% (9/9 cases).
      • 5d (PET evaluations on day of fraction delivery eliciting "Pass" signal): 94% (17/18 fractions).
    • Comparison of BgRT and SBRT PTV volumes: Average 23.1% volume reduction with BgRT.
    • Safety: 55.6% (5/9) experienced Any TEAEs. Most common were Investigations (33.3%), General disorders and administration site conditions (22.2%), and Musculoskeletal and connective tissue disorders (22.2%).

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

Non-clinical/Bench Studies:

• Coverage margin loss: ≤ 3mm acceptable.
• Dosimetric coverage: Dose at all the points measured on film within the CTV ≥ 97% of prescription dose, but ≤ 130% of maximum planned dose.
• Gamma Index (90% of comparison points within 3% in dose or closer than 3mm in 3D space)

Clinical Study (in silico):

• Cohort I:
  • Activity Concentration (AC): ≥ 5 kBq/ml met for BgRT functionality.
  • Overall % agreement (localization decision): 83.3% (5/6)
  • Positive % agreement (localization decision): 83.3%
  • Positive % agreement (plan proceed with 3rd party PET/CT): 100% (6/6)
  • Overall % agreement (plan proceed with 3rd party PET/CT): 83.3%
  • Negative % agreement (plan proceed with 3rd party PET/CT): 0
  • Percent of cases with acceptable BgRT plan: 67% (4/6)
  • Percent of cases meeting Gamma Index for dose distribution: 67% (4/6) overall, 100% (4/4) where acceptable plan was created.
• Cohort II:
  • Primary Endpoint (Emulated Delivery bDVH %): >95% for BTZ and OAR. Most fractions (17/18) passed.
  • Concordance (physical and digital phantoms via gamma index): 100% (18/18)
  • Overall % agreement (PET PreScan localization decision): 72.2% (13/18)
  • Positive % agreement (PET PreScan localization decision): 80%
  • Negative % agreement (PET PreScan localization decision): 33%
  • Positive % agreement (positive localization decision with 3rd party PET/CT): 100% (7/7)
  • Overall % agreement (positive localization decision with 3rd party PET/CT): 100%
  • Negative % agreement (positive localization decision with 3rd party PET/CT): N/A
  • Workflow: PET imaging sessions meeting AC threshold: 100% (18/18 fractions)
  • Workflow: PET imaging sessions leading to acceptable BgRT plans: 100% (9/9 cases)
  • Workflow: Approved BgRT plans passing physics quality assurance: 100% (9/9 cases)
  • Workflow: PET evaluations on the day of fraction delivery eliciting a "Pass" signal: 94% (17/18 fractions)
• Average % Volume Reduction with BgRT compared to SBRT: 23.1%

Predicate Device(s)

K190978

Reference Device(s)

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information

Not Found

Regulation Number and Section

N/A

Summary

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DE NOVO CLASSIFICATION REQUEST FOR REFLEXION MEDICAL RADIOTHERAPY SYSTEM (RMRS)

REGULATORY INFORMATION

FDA identifies this generic type of device as:

Fludeoxyglucose F18-guided radiation therapy system. A fludeoxyglucose F18guided radiation therapy system is a device that combines the functionality of an emission computed tomography detection system and a linear accelerator. The device is intended for use with approved fludeoxyglucose F18. The emission computed tomography detection system acquires images of positron-emitting fludeoxyglucose F18 for the purpose of guiding the delivery of megavoltage x-rays for oncologic treatment with radiation therapy using an FDA cleared, authorized, or approved linear accelerator.

NEW REGULATION NUMBER: 21 CFR 892.5060

CLASSIFICATION: Class II

PRODUCT CODE: QVA

BACKGROUND

DEVICE NAME: RefleXion Medical Radiotherapy System (RMRS)

SUBMISSION NUMBER: DEN220014

DATE DE NOVO RECEIVED: February 23, 2022

SPONSOR INFORMATION:

RefleXion Medical Inc 25841 Industrial Boulevard, Suite 275 Hayward. California 94545

INDICATIONS FOR USE

The RefleXion Medical Radiotherapy System (RMRS) is indicated as follows:

The RefleXion Medical Radiotherapy System is indicated for treatment planning and precise delivery of image-guided radiation therapy, stereotactic radiotherapy, or stereotactic radiosurgery for tumors or other targeted tissues anywhere in the body when radiation treatment is indicated. while minimizing the delivery of radiation to vital healthy tissue. The megavoltage X-ray radiation is delivered in a rotational, modulated, image-guided format in accordance with the physician approved plan.

1

The RefleXion Medical Radiotherapy System is also indicated for FDG-guided treatment which includes modeling, planning and precise delivery of FDG-guided radiation therapy, a type of Biology-guided Radiotherapy (BgRT), in five or fewer fractions for adults. It is indicated for tumor volumes in lung and bone subject to potential motion and positional uncertainty that have each been assessed with on-board PET/CT prior to delivery for adequate localization, sufficient FDG metabolic activity, local contrast and consistent biodistribution to meet the RMRS requirements, while minimizing the delivery of radiation to vital healthy tissue. BgRT involves the detection of signals from F18 during active beam delivery as a guide to deliver megavoltage X-ray radiotherapy in a rotational, modulated format in accordance with a physician approved treatment plan.

For complete fludeoxyglucose F18 prescribing information, refer both to the current medical imaging agent labeling and to this device labeling under "FDG Medical Imaging Agent Information".

LIMITATIONS

• . The sale, distribution, and use of the RMRS are restricted to prescription use in accordance with 21 CFR 801.109.
• . The clinical study did not include treatment of patients with the RMRS device, and instead assessed effectiveness through the use of data simulated in silico.
• . The quality of the positron emission tomography (PET) images obtained using the RMRS device are not of diagnostic quality. The PET system within the RMRS device is not intended to be used as a stand-alone diagnostic device.
• Clinical performance testing did not include an evaluation of the treatment of multiple . targets in a single treatment session.
• . The RMRS is not intended for use with radiopharmaceuticals other than fludeoxyglucose F18.
• . The biology-guided radiotherapy function requires a use of fludeoxyglucose F18 that is not in accordance with the currently approved prescribing information.
• . The exact dose to be delivered to the target prior to treatment is unknown. Bounded dose volume histogram (DVH), which is calculated using the planning PET scan, includes a range of uncertainty to account for possible variations in dosimetric outcomes during treatment.

PLEASE REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.

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DEVICE DESCRIPTION

The RMRS is a linear accelerator capable of delivering intensity-modulated radiation therapy, stereotactic body radiation therapy, stereotactic radiotherapy, stereotactic radiosurgery, and biology-guided radiotherapy (BgRT).

The RMRS is comprised of six major subsystems as shown in Figure 1.

Image /page/2/Figure/3 description: The image shows a large, complex piece of machinery, possibly a medical imaging device like a CT scanner or MRI machine. The machine has a circular opening in the center, surrounded by various electronic components, wiring, and mechanical parts. The numbers 1 through 6 are overlaid on the image, pointing to different sections of the machine, likely for identification or labeling purposes. The overall impression is one of advanced technology and intricate engineering.

Figure 1. The major subsystems of the RefleXion Medical Radiotherapy System are: 1) Compact linear accelerator, 2) primary collimation, 4) PET scanner, 5) kVCT, and 6) MV x-ray detectors.

The linear accelerator portion of the device was previously cleared under a 510(k) premarket notification (K190978). The subject device in K190978 included the PET hardware, but the PET hardware and associated software was inactive and outside the scope of K190978. The subject of the current submission is the addition of the BgRT functionality and the activation of the PET hardware.

Biology-guided Radiation Therapy

BgRT is a type of volumetric modulated arc therapy that allows radiation dose delivery in a slice-by-slice fashion using a multi-pass couch motion based on the collection and processing of

3

PET data from the radiotracer fludeoxyglucose F18 (FDG). BgRT also allows the dose delivery to be adjusted in real-time to account for target motion in the lung and bone.

The PET system is comprised of two PET detector arcs mounted on the ring gantry that rotate with the system to generate complete tomographic samples of radiotracer distribution required for the BgRT algorithm.

Rapidly acquired "limited time sampled" (LTS) PET imaging data are used to form accumulated lines of response (projection data). These data are then used to guide the beam using the mapping calculated during BgRT planning, maintaining the ability to track the target in real-time as it moves within a pre-defined volume called the biology-tracking zone (BTZ). The BTZ is the volume within which primary dose delivery is allowed. It encompasses the motion extent (internal target volume or ITV), biology-guidance margin (BgM) and the set-up margin (SM) (Figure 2). Unlike standard radiotherapy, the planning target volume (PTV) expansion for BgRT only includes the biology-guidance margin (BgM) and not the motion extent with internal margin (IM) or the set-up margin since the delivery tracks the PTV. The clinical target volume (CTV) and the gross tumor volume (GTV) are the same between BgRT and standard RT. The treatment delivery system uses the BTZ as a limiting factor in the delivery of the prescription dose.

Image /page/3/Figure/3 description: The image compares standard radiation therapy (RT) to biology-guided RT. The standard RT diagram shows nested regions labeled GTV, CTV, ITV, IM&SM, IM, and PTV. The biology-guided RT diagram shows nested regions labeled GTV, CTV, PTV, BgM, BgM&SM, BTZ, and motion extent. The diagrams illustrate how the target volumes and margins differ between the two approaches.

Figure 2. Comparison of volumes drawn for standard radiation therapy and BgRT.

In order to ensure sufficient FDG signal during planning and on the day of treatment, the treatment planning software calculates two quantitative parameters from the tumor PET image to determine whether BgRT is a viable option:

• . Activity Concentration (AC) - a minimum FDG activity concentration calculated by estimating the net signal concentration from the target.
• Normalized Target Signal (NTS) Calculated by taking the Activity Concentration . (focused on the target signal) normalized by the noise in the background around the BTZ.

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An AC of > 5 kBq/ml at the time of treatment planning and treatment delivery ensures sufficient counts in the LTS PET image to translate to accurate fluence (hence accurate dose). An NTS of ≥ 2.7 at the time of treatment planning and ≥ 2.0 at the time of treatment delivery ensures adequate PET tumor contrast (tumor signal to background) for the system to calculate the fluence for both the planning and treatment delivery.

Image /page/4/Figure/1 description: This image is a flowchart that outlines the steps involved in a medical simulation and treatment process. The flowchart is divided into five main stages: Simulation, Plan set-up, Imaging-only, Optimization & Evaluation, and Delivery. Each stage consists of several steps, such as importing patient data, setting optimization constraints, and performing PET injections. The flowchart also indicates which steps are performed by an external system and which are unique to BgRT.

Clinical Workflow

Figure 3. Clinical workflow using BgRT

Step 1: Using patient data obtained from an external system PET/CT, users draw contours on a simulation CT on third-party software. Contours include the BTZ in addition to other target contours. The RefleXion treatment planning station allows the user to import the resulting CT DICOM image set and the DICOM RT structure set, which includes contours for the appropriate volumes.

Step 2: The detailed treatment plan is developed (typically by a medical physicist or dosimetrist) using the RefleXion treatment planning software, providing estimated dose volume histograms and other dosimetric measures. The radiation oncologist must approve the treatment plan, which is then saved in the RefleXion database and available at the operator console. The medical physicist conducts patient-specific quality assurance of the treatment plan and must approve the treatment plan prior to proceeding.

• . Step 2a (BgRT only): If the patient is a candidate for BgRT, an initial plan will be created and approved for an "Imaging-only" session on the RMRS. This plan is used to collect the pre-treatment planning PET image (a RefleXion planning PET image) that will be used in the remaining treatment planning process.
• . Step 2b (BgRT only): FDG is administered at an appropriate time prior to the Imagingonly session. FDG has a half-life of 109.7 minutes, and an injection of 15 mCi is recommended. Typically, the injection is administered in an "uptake" room, where the

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patient sits quietly for approximately one hour after injection. The patient then proceeds to the radiotherapy delivery suite.

• . Step 2c (BgRT only): The patient is positioned on the treatment couch using lasers for initial alignment and then the kVCT subsystem is used to check patient positioning. The planning PET image is acquired.
• . Step 2d (BgRT only): With the planning PET image available in the treatment planning system, the radiation oncologist will decide, based on the metabolic characteristics (which include AC and NTS) of the target volume. whether radiotherapy delivery with PET guidance is warranted. If so, the planning PET image is used to create a BgRT plan.

Step 3 (BgRT only): The plan is then optimized and evaluated using DVHs that are specific to the BgRT workflow called bounded DVHs (bDVHs).

• Step 3a (BgRT only): If the plan is considered satisfactory, and the BgRT metrics . (activity concentration and normalized target signal) are met, the plan can then go through patient-specific plan QA, be approved, and used for treatment delivery.
  Step 4 (BgRT only): Patients receiving BgRT will have the FDG iniection (15 mCi) prior to each treatment fraction. Typically, the injection is administered in an "uptake" room, where the patient sits quietly for approximately one hour after iniection. The patient then proceeds to the radiotherapy delivery suite.

Step 5: At the time of treatment, the patient is positioned on the treatment couch. Lasers assist in the initial patient alignment. The kVCT system will be used for every fraction to obtain kVCT images for use in checking patient positioning against the treatment plan. After the clinical staff confirms satisfactory alignment of the kVCT images with the planning CT image, any necessary couch shifts can be applied.

Step 5 (BgRT Only): For cases where PET information is being used to guide the radiotherapy, after the patient is positioned using the kVCT system, a PET pre-scan of the patient is conducted immediately prior to delivering radiation to confirm that the PET information acquired on the day of treatment is consistent with the PET information used to develop the treatment plan. The PET evaluation must pass for the patient to proceed to treatment delivery. The physician also must confirm the alignment of the PET signal with the appropriate contours before moving to treatment delivery.

Step 6: After the kVCT and PET pre-scan imaging is complete, the couch moves longitudinally through the bore of the gantry to the starting position at the therapy plane and then the radiotherapy begins according to the treatment plan.

• Step 6a (BgRT Only): During BgRT delivery, LTS PET images are used to provide . tracked dose delivery to the PTV, which can account for positional offsets or tumor motion during treatment (for example, patient respiration, peristalsis, or voluntary movement).

6

Step 7: After the therapy is completed, the delivered dose is recorded and verified. The delivered dose distribution (calculated from the delivered beamlet sequence) can be generated and reviewed on the Treatment Planning system. The post-treatment PET image (i.e., the PET image generated from all emission data collected during the treatment delivery) can also be reviewed on the Treatment Planning system at this time.

SUMMARY OF NONCLINICAL/BENCH STUDIES

BIOCOMPATIBILITY/MATERIALS

The patient contacting components are unchanged from the cleared linear accelerator compatible with this system (K190978).

SHELF LIFE/STERILITY

No components of the device are provided sterile. Reprocessing instructions are unchanged from the cleared linear accelerator compatible with this system (K190978).

ELECTROMAGNETIC COMPATIBILITY & ELECTRICAL SAFETY

Electrical safety and electromagnetic compatibility testing were performed per the following standards and was found to be acceptable:

• ANSI AAMI ES60601-1:2005/(R)2012 and A1:2012, C1:2009/(R)2012 and . A2:2010/(R)2012 (Consolidated Text) Medical electrical equipment - Part 1: General requirements for basic safety and essential performance
• . IEC 60601-1-2 Edition 4.0 2014 Medical electrical equipment - Part 1-2: General requirements for basic safety and essential performance - Collateral Standard: Electromagnetic disturbances - Requirements and tests
• IEC 60601-1-3 Edition 2.1 2013 Medical electrical equipment Part 1-3: General . requirements for basic safety and essential performance - Collateral Standard: Radiation protection in diagnostic x-ray equipment
• . IEC 60601-1-6 Edition 3.1 2013 Medical electrical equipment - Part 1-6; General requirements for basic safety and essential performance - Collateral standard: Usability
• . IEC 60601-2-1 Edition 3.1 2014 Medical electrical equipment - Part 2-1: Particular requirements for the basic safety and essential performance of electron accelerators in the range 1 MeV to 50 MeV
• EC 60601-2-44 Edition 3.2: 2016 Medical electrical equipment Part 2-44: Particular . requirements for the basic safety and essential performance of x-ray equipment for computed tomography
• IEC 60601-2-68 Edition 1.0 2014 Medical electrical equipment Part 2-68: Particular . requirements for the basic safety and essential performance of x-ray-based image-guided radiotherapy equipment for use with electron accelerators, light ion beam therapy equipment and radionuclide beam therapy equipment

7

SOFTWARE

The RMRS software documentation and testing provided demonstrate that the device meets all requirements outlined in the FDA "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices" for software of major level of concern.

| Test | Purpose | Method | Performance Metrics
and Acceptance
Criteria | Results |
|--------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Moving target
with 3-D
respiratory and
3-D non-
respiratory
motion; organs
at risk (OARs)
independent
motion | To demonstrate the
BgRT dose delivery
accuracy to target(s)
and measure dose to
OARs with respiratory
or non-respiratory
continuous motion
pattern:
• BgRT dose delivery
accuracy to target
and nearby normal
tissues (OARs)
• BgRT dose delivery
accuracy for varying
degrees of clinical
motion patterns
• Comparison with
stereotactic body
radiation therapy
(SBRT) treatment
delivery | Tests were performed
with a large
anthropomorphic
phantom. The
background consisted
of water with FDG to
simulate an FDG-active
background. Two arms
were included that
could be programmed
with distinct motion
patterns. Inserts of
varying shape/size were
injected with FDG to
simulate targets or
OARs. The shapes
included sphere, C-
shape, and ovoid. The
C-shape and sphere
OARs were used for
respiratory motion tests,
and the ovoid was used
for the non-respiratory
motion test. | Coverage margin loss -
The maximum of
(CMP-CMD* in a
given plane) for all
planes in 3D space. The
acceptance criterion for
coverage margin loss is
≤ 3mm.
Dosimetric coverage -
Dose at all the points
measured on film
within the CTV ≥ 97%
of prescription dose,
but ≤ 130% of
maximum planned
dose.
For the OAR, two
measurements were
made. A point dose
measurement was made
by a calibrated ion
chamber and was
required to be less than
or equal to the expected
plan dose as a
quantitative dose check.
In addition, the
maximum dose
measured on the
radiochromic film
inserted into the OAR
structure was required
to be less than the
maximum plan dose as
a qualitative dose
check. | Both dosimetric
coverage criteria as
well as OAR dose
criteria were met for all
BgRT test cases.
Under the same test
circumstances, SBRT
plans with an ITV
approach for the target
were not able to
successfully meet the
same criteria as the
BgRT plans. |
| Target or OAR
with a single
step shift - | To demonstrate the
BgRT dose delivery
accuracy to target(s) | Same methodology as
described above. A
specific OAR shape | Same acceptance
criteria as described
above. | Both dosimetric
coverage criteria as
well as OAR dose |
| (positional
uncertainty) | OARs in the case of a
single step shift of the
target:
• Effectiveness of
BgRT treatment
providing conformal
dose to the target
while sparing nearby
normal tissues
(OARs)
• BgRT dose delivery
accuracy
• Comparison with
SBRT treatment
delivery | was not utilized for this
test. | criteria were met for all
BgRT test cases.

Under the same test
circumstances, SBRT
plans with an ITV
approach for the target
were not able to
successfully meet the
same criteria as the
BgRT plans. | |
| Test clinical
variations of
targets
(stationary) | To demonstrate the
BgRT dose delivery
accuracy for various
clinical situations:
• Various target-to-
background (T:B)
contrast
• Different FDG
biodistribution
patterns between
planning and
delivery while
keeping the same
anatomic shape of
the target
• Test homogenous or
heterogenous
backgrounds around
the target | The phantom used in
the stationary tests was
the ArcCHECK Model
(b)(4) | PET evaluation results
(AC/NTS/bDVH).

Bounded DVH – 95%
of points in the
calculated dose DVHs
of all static structures
must be within the
bounds of the bDVH
from the treatment plan.

Gamma Index - This
method compares the
plan dose extrapolated
to all points in space
represented by the
(calibrated) detector
diodes. The acceptance
criteria chosen for these
tests required that 90%
of the comparison
points (that were above
10% of the prescription
dose) were within either
3% in dose or closer
than 3mm in 3D space
(DTA or distance to
agreement) to a point
with the same dose.

Acceptance criteria
requires both the PET
Evaluation to pass and
either post-delivery
DVH to have ≥ 95% of
the points fall within
the bounds of the
treatment plan and/or
the Gamma index to be
above 90% | For all tests where the
acceptance criteria
required both the PET
evaluation to pass and
either the post-
treatment dose
evaluation against the
plan and/or the Gamma
index to pass met the
dose accuracy criteria.
For cases where there
was a significant
change in
biodistribution in the
target, low contrast
between the target and
background, or a
change in the
background signal, the
PET evaluation did not
pass, and the resulting
dose accuracy showed
mixed results. |
| Tests evaluating
special edge
cases
(stationary) | To demonstrate
robustness of the BgRT
system under
challenging situations:
• Variations between
planning and
delivery such as
changes in PET
biodistribution
patterns
• PET-avid OAR in the
BTZ prior to delivery
• Dose delivery
accuracy to target in
the presence of
nearby PET-avid
OAR.
• PET Evaluation step
challenge with large
changes between
planning and
delivery | Same methodology as
described above with
stationary tests. | Same acceptance
criteria as described
above with stationary
tests. | For cases where there
was a significant
change in
biodistribution between
planning and delivery,
or a situation when an
FDG-avid target moves
into the BTZ, the PET
evaluation did not pass. |
| BgRT ON/OFF
with Motion
ON/OFF | To demonstrate the
benefit of BgRT in the
same test setup by
running with BgRT ON
compared to BgRT
OFF.
• BgRT dose delivery
accuracy to target
and measure dose to
OAR with
respiratory
continuous motion
pattern for the target
• BgRT dose delivery
accuracy to target
and measure dose to
OAR in the case of a
single shift of the
target | Same phantom as used
with the motion tests
described above. The
C-shape was used for
respiratory motion tests,
and the sphere was used
for the non-respiratory
motion test. | Coverage margin loss -
The maximum of
(CMP-CMD* in a
given plane) for all
planes in 3D space. The
acceptance criterion for
coverage margin loss is
≤ 3mm.
Dosimetric coverage -
Dose at all the points
measured on film
within the CTV ≥ 97%
of prescription dose,
but ≤ 130% of
maximum planned
dose.
For nearby OARs, the
maximum dose will be
measured using
radiochromic film over
all valid dose points
and the acceptance
criteria is that the
maximum dose
measured on the film
must be below a value
that is 3% higher than
the bDVH maximum
dose as calculated by
the plan. | BgRT ON Motion ON -
The tracked dose
delivery was
successfully provided
where the CTV was
fully covered (100%) in
all cases. In cases for
which the PET
evaluation did not pass,
some degradation to
margin loss was
observed.
BgRT OFF Motion ON

• In all cases dose
  accuracy failed the
  criteria. The CTV dose
  coverage was less than
  100% and margin loss
  higher than 3.0mm.
  BgRT ON Motion OFF
• All test cases met the
  dose accuracy criteria.
  BgRT OFF Motion
  OFF - All test cases
  met the dose accuracy
  criteria. |
  | Multi-target
  testing | To determine accuracy
  of delivery with cases
  of lower target to
  background contrast | Same methodology as
  motion testing. | Coverage margin loss -
  The maximum of
  (CMP-CMD* in a
  given plane) for all
  planes in 3D space. The
  acceptance criterion for
  coverage margin loss is
  ≤3mm.

Dosimetric coverage -
Dose at all the points
measured on film
within the CTV ≥ 97%
of prescription dose,
but ≤ 130% of
maximum planned
dose | For all 3-target, moving
tests, including with
reduced target:
background for the
second and third
targets, all dosimetric
criteria (CTV dose
coverage and Margin
Loss) were met. |

PERFORMANCE TESTING - BENCH

8

9

10

• Coverage margin planning (CMP) - The distance (in any plane) from the CTV contour to the 97% isodose contour in a treatment plan. The target was considered "covered" in the treatment plan if 100% of the PTV receives 97% of the dose. Coverage margin delivery (CMD) - The distance (measured in any plane, but usually LR, SI, AP) from the CTV contour to 97% delivered dose contour measured (usually from film) in the reference frame of the target (that is, on a moving phantom)

Verification testing was performed for the PET subsystem to assess the following:

• PET NEMU NU-2 performance tests for spatial resolution, scatter fraction and count rate . measurements, sensitivity, and image quality
• PET System Performance Checks .
• . PET image reconstruction and attenuation correction

All tests passed the pre-defined acceptance criteria.

Verification testing was performed to assess the performance and integration of the following subsystems:

• . kVCT
• . MV x-ray detectors (MVD)
• Beamgen .
• Collimation .
• Couch .
• Treatment planning .
• Treatment delivery .

Testing was performed in accordance with the following standards and found to be acceptable:

• IEC 62368-1 / UL 62368-1:2014 Ed.2 Audio/video, information and . communication technology equipment - Part 1: Safety requirements
• IEC 61217 Edition 2.0 2011 Radiotherapy equipment Coordinates, movements. . and scales
• IEC 62083 Edition 2.0 2009 Medical electrical equipment Requirements for the . safety of radiotherapy treatment planning systems
• . IEC 62274 First Edition 2005 Medical electrical equipment - Safety of radiotherapy record and verify systems

11

• IEC 60976 Edition 2.0 2007 Medical electrical equipment Medical electron . accelerators - Functional performance characteristics
• NEMA NU 2-2018 Performance Measurements of Positron Emission . Tomographs

SUMMARY OF CLINICAL INFORMATION

A single-arm, prospective, IDE clinical trial was conducted at two sites in the U.S. The study was conducted using two cohorts, and the population included adults 21 years or older with at least 1 active tumor in the bone or lung.

Cohort I

• Primary Objective: To identify the Recommended RefleXion FDG Dose (RRFD) that . enables the use of BgRT on the RMRS.
  • · Primary Endpoint: The FDG dose that results in Activity Concentration necessary for BgRT functioning (i.e., 5 kBq/ml or higher).
• Secondary Objective: To assess the performance of the BgRT PET imaging-only session, . treatment planning and quality assurance at the studied dose level.
  • o Secondary Endpoints
    • 1. Percent of cases where there was an agreement between a site investigator (SI) and agreement standard (AS) for the BgRT PET imaging-only session localization decision (overall percent agreement). Positive percent agreement and negative percent agreement are also reported.
    • 2. Percent of cases where there was concordance of the positive "plan proceed" decision between the BgRT imaging-only session PET and a cleared, thirdparty diagnostic PET/CT (positive percent agreement). Overall percent agreement and negative percent agreement are also reported.
    • 3. Percent of cases where RefleXion PET data could be used to generate an acceptable BgRT plan such that relevant dosimetric parameters for the target and the nearby normal anatomy were met based on Investigator assessment.
    • 4. Percent of cases where the intended dose distribution of the BgRT plan was achieved in a physical phantom, defined as meeting a standard gamma index for external beam radiotherapy quality assurance, i.e., whether 90% of pixels meet the 3 mm/3% deviation standard.
• Study design .
  • This cohort sought to identify the Recommended RefleXion FDG dose (RRFD). o which is the dose of administered FDG that allows for functioning of the RMRS. This cohort also sought to assess RMRS PET imaging performance in comparison to a third-party diagnostic PET/CT.
  • The dose levels of 15 mCi and 20 mCi were to be assessed sequentially in an o escalation protocol (note that 15 mCi was found sufficient and thus the study never progressed to the 20 mCi dose level). Patients with at least one known FDG avid tumor (i.e., SUVmax ≥ 6 on diagnostic PET/CT) in the bone or lung were enrolled into this cohort.

12

• These patients underwent a CT simulation in an acceptable radiotherapy treatment o position and with immobilization devices as needed. After acquisition of (4D)CT images, contours for targets, OARs, and BTZ were be generated by the investigator.
• Next, the patient underwent back-to-back PET scans on the RMRS device and a thirdo party diagnostic PET/CT device after a single injection of FDG at the studied FDG dose level
• Quantitative metrics were collected for each lesion to assess the performance of the o RMRS PET subsystem.
• The demographics of Cohort I are listed in Table 1. .

Demographic	Cohort I (n=8)
Age (years)	$64.6 \pm 14.01$
Gender	Female: 12.5% (1)
Ethnicity	Not Hispanic or Latino: 100% (8)
Race	Asian: 25% (2)
	Black or African American: 12.5% (1)
	White: 50% (4)
	Unknown: 12.5% (1)
Baseline ECOG
performance status	ECOG 1: 62.5% (5)
ECOG 2: 37.5% (3)
Baseline height (cm)	$176.6 \pm 8.33$
Baseline weight (kg)	$67.43 \pm 15.257$
Baseline BMI (kg/m²)	$21.47 \pm 3.803$
Cancer type	Bone: 62.5% (5)
Lung: 37.5% (3)
Tumor size (cm)	$2.71 \pm 0.831$
Cancer stage	IV: 75% (6)
Unknown: 25% (2)

Table 1. Cohort I Demographics

• The results from the primary endpoint are displayed in Table 2. .

| Tumor type | Planned Dose
(mCi) | Actual Dose*
(mCi) | Activity
Concentration
(kBq/ml) | Met the Threshold
for BgRT? |
|------------|-----------------------|-----------------------|---------------------------------------|--------------------------------|
| Lung | 15 | 15.46 | 8.87 | Yes |
| Lung | 15 | 15.12 | 7.46 | Yes |
| Lung | 15 | 16.37 | 21.05 | Yes |
| Bone | 15 | 15.52 | 14.61 | Yes |
| Bone | 15 | 14.64 | 11.27 | Yes |
| Bone | 15 | 17.70 | 18.47 | Yes |

Table 2, Cohort I Primary Endpoint Results

• A variance of 10% was pre-defined as acceptable based on typical practice.

13

• The results from the secondary endpoints are displayed in Table 3. Of the 8 patients enrolled, . 6 had evaluable images.

Endpoint #	Description	Result
1	Percent of cases where there was an agreement
between a SI and AS for the BgRT PET imaging-
only session localization decision (overall
percent agreement).	Overall % agreement = 83.3% (5/6)
Positive % agreement = 83.3%
Negative % agreement = N/A
2	Percent of cases where there was concordance of
the positive “plan proceed” decision between the
BgRT imaging-only session PET and a cleared,
third-party diagnostic PET/CT (positive percent
agreement).	Positive % agreement = 100% (6/6)
Overall % agreement = 83.3%*
Negative % agreement = 0
3	Percent of cases where RefleXion PET data
could be used to generate an acceptable BgRT
plan such that relevant dosimetric parameters for
the target and the nearby normal anatomy were
met based on Investigator assessment.	67% (4/6)
4	Percent of cases where the intended dose
distribution of the BgRT plan was achieved in a
physical phantom, defined as meeting a standard
gamma index for external beam radiotherapy
quality assurance, i.e., whether 90% of pixels
meet the 3 mm/3% deviation standard.	67% (4/6)
100% (4/4) for all cases where an
acceptable plan was created.

Table 3. Cohort I Secondary Endpoint Results

• The overall % agreement for the aggregate radiation oncologist review was 83.3% (5/6) due to one case in which localization was not established on the RMRS device even though it was established on the diagnostic PET/CT.

• The safety results from Cohort I are shown in Table 4. The Safety Population were the . participants who received any FDG dose for RefleXion Imaging-only session.
  Table 4. Cohort I Safety Results

| System Organ Class
Preferred Term | Dose Level 1
(15 mCi)
(n=8)
n (%) |
|-------------------------------------------------|--------------------------------------------|
| Any TEAEs | 5 (62.5) |
| Musculoskeletal and connective tissue disorders | 4 (50.0) |
| Back pain | 2 (25.0) |
| Arthralgia | 1 (12.5) |
| Neck pain | 1 (12.5) |
| Pain in extremity | 1 (12.5) |
| Gastrointestinal disorders | 3 (37.5) |
| Nausea | 2 (25.0) |
| Oral dysaesthesia | 1 (12.5) |
| Metabolism and nutrition disorders | 1 (12.5) |
| Decrease appetite | 1 (12.5) |

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Nervous system disorders	1 (12.5)
Somnolence	1 (12.5)

% = 100 x n/N, where N = number of participants in the given study group in the population and n = number of participants in a specified category.

A TEAE was defined as any AE that started on or after the first dose of FDG or occurred prior to the first dose and worsened in severity on or after the first dose of FDG, during the treatment period and follow-up period. AE = adverse event: FDG = fludeoxyglucose. PT = preferred term: SOC = system organ class; TEAE = treatment emergent adverse event

Cohort II

• Primary Objective: To determine whether BgRT dose distributions generated from LTS PET . images obtained at the time of treatment delivery are consistent with the approved BgRT plan.
  • Primary Endpoint: The percent of radiotherapy fractions where the emulated BgRT o dose distribution in silico was shown to be consistent with the approved BgRT treatment plan (i.e., 95% of DVH Delivered points for the BTZ and organ-at-risk [OAR] fell within bounded DVH of the approved BgRT plan).
• . Secondary Objective: To emulate and confirm deliverability of the fluence associated with the BgRT dose distribution generated from LTS PET images obtained at the time of treatment delivery as well as to assess imaging, process and safety characteristics of the endto-end workflow.
  • O Secondary Endpoints:
    • 1. Percent of fractions where there was concordance between the physical and digital phantoms of emulated BgRT delivery derived from human participant PET emissions. Concordance was defined as a standard gamma index with a goal that 90% of pixels met the 3 mm/3% deviation standard.
    • 2. Percent of cases where there was agreement between a SI and the AS for the BgRT PET PreScan localization decision (overall percent agreement). Positive percent agreement and negative percent agreement are also reported.
    • 3. Percent of cases where there was concordance of a positive localization decision between the short duration PET PreScan and a third-party diagnostic PET/CT scan (positive percent agreement). Overall percent agreement and negative percent agreement are also reported.
    • 4. Safety of multiple FDG administrations and toxicity rates of bladder and bone marrow assessed by complete blood counts (CBCs), urinalysis, and adverse events (AEs) specific to bladder and bone marrow assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 at 72 ± 24 hours after final FDG injection.
    • 5. Workflow characterization:
      • a. Percent of PET imaging sessions at RRFD that met the AC threshold for BgRT (5 kBq/mL);
      • b. Percent of PET imaging sessions which led to acceptable BgRT plans, with acceptability based upon meeting user-defined coverage goals for tumor targets and avoidance goals for OARs:

15

• c. Percent of approved BgRT plans that went on to pass physics quality assurance, as defined by 90% of pixels meeting the 3 mm/3% deviation standard: and
• d. Percent of PET evaluations on the day of fraction delivery that elicited a "Pass" signal.
• Study design .
  • · This cohort sought to confirm that the machine-deliverable fluence generated by applying the BgRT firing filter to PET LTS images obtained at the time of a radiotherapy delivery does in fact result in an anatomic dose distribution that is consistent with the approved BgRT plan. It also sought to confirm that the linear accelerator subsystem hardware is able to deliver the received machine instructions. The purpose was to emulate and assess (without actually delivering the radiation therapy to the patient) the entire end-to-end BgRT workflow from simulation to treatment planning to, finally, dose delivery.
  • Patients dispositioned to undergo conventional SBRT for a single bone tumor or a o single lung tumor were enrolled. For each patient, RMRS PET collections were added to the SBRT workflow at 3 timepoints representing the steps when the RMRS PET subsystem would be utilized during the BgRT workflow. Specifically, these timepoints included a RMRS PET imaging-only session prior to the start of SBRT delivery that was used to create a BgRT plan as well as RMRS PET collections before the first and final fractions of their planned course of SBRT. A single comparison third-party diagnostic PET/CT image was obtained (utilizing the same FDG injection) on the day of the final fraction.
  • In order to emulate BgRT delivery, each of these fractional PET collections consisted of two phases:
    • 1. Short-duration PET collection that corresponds to the duration of a PET PreScan Evaluation
    • 2. Long-duration PET collection that corresponds to the duration of an active BgRT delivery fraction
    • · The long-duration PET collection data mimics RefleXion LTS PET image acquisition during live BgRT and was therefore used to determine the hardware instructions that would be transmitted to the RMRS delivery hardware (linear accelerator, gantry, MLC, etc.) based upon the algorithmic interaction between the incoming LTS images and the approved BgRT treatment plan.
• The demographics of Cohort II are listed in Table 5. .

Demographic	Bone Tumors (n=4)	Lung Tumors (n=5)	Total (n=9)
Age (years)	69.5 ± 9.81	69.6 ± 12.44	69.6 ± 10.65
Gender	Female: 0%	Female: 40% (2)	Female: 22.2% (2)
Ethnicity	Not Hispanic or Latino:
100% (4)	Not Hispanic or Latino:
80% (4)	Not Hispanic or Latino:
88.9% (8)

Table 5. Cohort II Demographics

16

| | | Hispanic or Latino: 20%
(1) | Hispanic or Latino: 11.2%
(1) |
|----------------------------------------|---------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------|
| Race | Black or African
American: 25% (1)
White: 75% (3) | Black or African
American: 40% (2)
White: 40% (2)
American Indian or
Alaskan Native: 20% (1) | Black or African
American: 33.3% (3)
White: 55.6% (5)
American Indian or
Alaskan Native: 11.1% (1) |
| Baseline ECOG
performance
status | ECOG 0: 75% (3)
ECOG 1: 25% (1) | ECOG 0: 40% (2)
ECOG 1: 40% (2)
ECOG 2: 20% (1) | ECOG 0: 55.6% (5)
ECOG 1: 33.3 (3)
ECOG 2: 11.1 (1) |
| Baseline height
(cm) | 177.3 ± 5.91 | 170.8 ± 7.60 | 173.7 ± 7.31 |
| Baseline weight
(kg) | 92.05 ± 14.563 | 85.78 ± 17.208 | 88.57 ± 15.444 |
| Baseline BMI
(kg/m $^{2}$ ) | 29.21 ± 3.389 | 29.58 ± 6.350 | 29.42 ± 4.950 |
| Cancer type | Primary bone: 25% (1)
Metastatic bone: 25% (1)
Primary lung: 25% (1)
Metastatic lung: 0%
Other: 25% (1) | Primary bone: 0%
Metastatic bone: 0%
Primary lung: 80% (4)
Metastatic lung: 20% (1)
Other: 0% | Primary bone: 11.1% (1)
Metastatic bone: 11.1%
(1)
Primary lung: 55.6 (5)
Metastatic lung: 11.1% (1)
Other: 11.1% (1) |
| Tumor size (cm) | 2.70 ± 0.735 | 2.46 ± 0.541 | 2.57 ± 0.604 |
| Cancer stage | IV: 100% (4) | II: 20% (1)
IV: 20% (1)
Unknown: 60% (3) | II: 11.1% (1)
IV: 55.6% (5)
Unknown: 33.3% (3) |

• The results from the primary endpoint are displayed in Table 6. .

| Tumor type | Imaging-Only Session Metrics | | Fraction | Emulated
Delivery
bDVH% (>95) | Result |
|------------|------------------------------|-------|----------|-------------------------------------|--------|
| | AC kBq/ml | NTS | | | |
| Lung | 24.52 | 22.75 | First | 99.9 | Pass |
| Lung | | | Last | 100 | Pass |
| Lung | 5.6 | 2.76 | First | 94.52 | Fail |
| Lung | | | Last | * | * |
| Lung | 41.58 | 18.59 | First | 96.37 | Pass |
| Lung | | | Last | 100 | Pass |
| Lung | 5.43 | 2.97 | First | 100 | Pass |
| Lung | | | Last | 100 | Pass |
| Lung | 6.67 | 4.37 | First | 99.7 | Pass |
| Lung | | | Last | 97.6 | Pass |
| Bone | 13.15 | 7.03 | First | 100 | Pass |
| Bone | | | Last | 99.61 | Pass |
| Bone | 9.82 | 3.93 | First | 100 | Pass |
| Bone | | | Last | 100 | Pass |
| Bone | 8.67 | 4.42 | First | 99.6 | Pass |

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			Last	100	Pass
Bone	10.94	6.24	First	100	Pass
			Last	100	Pass

• Last fraction was not evaluable as the PET Evaluation did not pass.

• The results from the secondary endpoints are displayed in Table 7. .

Table 7. Cohort II Secondary Endpoint Results
-----------------------------------------------

#	Description	Result
1	Percent of fractions where there was concordance
between the physical and digital phantoms of emulated
BgRT delivery derived from human participant PET
emissions. Concordance was defined as a standard
gamma index with a goal that 90% of pixels met the 3
mm/3% deviation standard.	100% (18/18)
2	Percent of cases where there was agreement between an
SI and the AS for the BgRT PET PreScan localization
decision (overall percent agreement).	Overall % agreement = 72.2%
(13/18)
Positive % agreement = 80%
Negative % agreement = 33%
3	Percent of cases where there was concordance of a
positive localization decision between the short-duration
PET PreScan and a third-party diagnostic PET/CT scan
(positive percent agreement).	Positive % agreement = 100%
(7/7)
Overall % agreement = 100%
Negative % agreement = N/A
4	Safety of multiple FDG administrations and toxicity
rates of bladder and bone marrow.	The reported events were
documented by the investigator
as not being related to the study
device or FDG injection. None
resulted in discontinuation of the
subject in the study.
Sa	Workflow: Percent of PET imaging sessions at RRFD
that met the AC threshold for BgRT (5 kBq/mL)	100% (18/18 fractions)
5b	Workflow: Percent of PET imaging sessions which led
to acceptable BgRT plans.	100% (9/9 cases)
5c	Workflow: Percent of approved BgRT plans that went
on to pass physics quality assurance.	100% (9/9 cases)
રવ	Workflow: Percent of PET valuations on the day of
fraction delivery that elicited a "Pass" signal	94% (17/18 fractions)

In addition to the analyses above, the sponsor also compared the BgRT and SBRT PTV . volumes (Table 8) to determine if there was a reduction in PTV by using the BgRT treatment paradigm.

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| Target tumor
location | BgRT (PTV)
(cc) | SBRT (PTV or
IPTV) (cc) | Absolute
Volume
Reduction
with BgRT
(cc) | % Volume
Reduction
with BgRT |
|--------------------------|--------------------|----------------------------|------------------------------------------------------|------------------------------------|
| Bone | 23.18 | 42.42 | 19.24 | 45.36% |
| Bone | 17.00 | 17.40 | 0.40 | 2.30% |
| Bone* | 53.35 | 96.60 | 43.25 | 44.77% |
| Bone | 14.90 | 15.00 | 0.10 | 0.67% |
| Lung | 8.76 | 14.19 | 5.43 | 38.27% |
| Lung | 12.40 | 19.97 | 7.57 | 37.91% |
| Lung | 41.30 | 47.30 | 6.00 | 12.68% |
| Lung | 49.20 | 49.00 | -0.20 | -0.41% |
| Lung | 12.50 | 16.90 | 4.40 | 26.04% |
| | | | Average | 23.1% |

Table 8. Comparison of BgRT and SBRT volumes

• In accordance with the protocol, a single lesion with a circumferential margin was used for the BgRT plan 101-015. However, for the SBRT plan, the site clinicians opted to treat to a larger target volume to cover more of the pelvic bone housing the lesion based on their clinical judgment (as opposed to the strict circumferential margin applied to BgRT). As a result, the difference in PTV volumes is especially marked in this case (96.6 cc for SBRT v. 43.25 cc for BgRT). Also, two nearby lesions in the pelvis were also treated during the SBRT course for this patient, resulting in an aggregate PTV volume of 143.2 cc when the contributions from all 3 lesions were summed.

• The safety results from Cohort II are shown in Table 9. The Safety Population (i.e., all . participants who received any amount of FDG dose for the RefleXion Imaging-only session) included 9 participants for Cohort II.

	Bone Tumors	Lung Tumors	Total
System Organ Class	(N=4)	(N=5)	(N=9)
Preferred Term	n (%)	n (%)	n (%)
Any TEAEs	3 (75.0)	2 (40.0)	5 (55.6)
Investigations	2 (50.0)	1 (20.0)	3 (33.3)
Blood creatinine increased	1 (25.0)	0 (0.0)	1 (11.1)
Lymphocyte count decreased	0 (0.0)	1 (20.0)	1 (11.1)
Platelet count decreased	1 (25.0)	0 (0.0)	1 (11.1)
White blood cell count decreased	1 (25.0)	0 (0.0)	1 (11.1)
General disorders and administration site conditions	2 (50.0)	0 (0.0)	2 (22.2)
Fatigue	2 (50.0)	0 (0.0)	2 (22.2)
Musculoskeletal and connective tissue disorders	1 (25.0)	1 (20.0)	2 (22.2)
Arthralgia	1 (25.0)	0 (0.0)	1 (11.1)
Back pain	1 (25.0)	0 (0.0)	1 (11.1)
Pain in extremity	0 (0.0)	1 (20.0)	1 (11.1)
Blood and lymphatic system disorders	1 (25.0)	0 (0.0)	1 (11.1)
Anaemia	1 (25.0)	0 (0.0)	1 (11.1)
Renal and urinary disorders	1 (25.0)	0 (0.0)	1 (11.1)
Pollakiuria	1 (25.0)	0 (0.0)	1 (11.1)
Reproductive system and breast disorders	1 (25.0)	0 (0.0)	1 (11.1)

Table 9. Cohort II Safety Results

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Prostatic obstruction	1 (25.0)	0 (0.0)	1 (11.1)
Skin and subcutaneous tissue disorders	1 (25.0)	0 (0.0)	1 (11.1)
Pain of skin	1 (25.0)	0 (0.0)	1 (11.1)

• For both Cohort I and Cohort II, the shifts applied during alignment of the PET scan with the . CT were calculated (Table 9). Overall. 5 out of 16 had PET alignment shifts (31.3%). The largest shift applied in any of the standard directions (lateral, anterior-posterior, or superiorinferior) was 4.7 mm. The largest total shift was 6.0 mm.

Applied PET Shifts
Cohort	Target
tumor
location	Lateral
(mm)	Ant-Post
(mm)	Sup-Inf
(mm)	Calculated
Total shift
(mm)
Cohort I	Bone	0	-3.0	2.0	3.6
Cohort I	Lung	-3.4	2.3	1.7	4.4
Cohort I	Lung	-0.9	3.6	4.7	6.0
Cohort II	Lung	3.0	0	1.1	3.2
Cohort II	Lung	1.0	0	3.0	3.2

Table 10. Cohort I and II PET alignment shifts

Pediatric Extrapolation

In this De Novo request, existing clinical data were not leveraged to support the use of the device in a pediatric patient population.

TRAINING

Training is required for the BgRT treatment paradigm. The sponsor provided a training program, which includes these key elements:

• . Determining patient eligibility
• Treatment planning .
• . Treatment delivery

LABELING

The labeling consists of Instructions for Use and packaging labels. The Instructions for Use include the indications for use; a description of the device including an Imaging Agent section to describe the new use of fludeoxyglucose F18; contraindications, warnings, precautions; a detailed summary of the non-clinical and clinical data collected in support of the device: and instructions for the safe use of the device. The labeling satisfies the requirements of 21 CFR 801.109.

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RISKS TO HEALTH

The table below identifies the risks to health that may be associated with use of the fludeoxyglucose F18-guided radiation therapy system and the measures necessary to mitigate these risks.

Risks to Health	Mitigation Measures
Device-specific modifications of
fludeoxyglucose F18 use compared to the
current approved drug label that affect safety
and effectiveness of fludeoxyglucose F18	Clinical performance testing
Labeling
Analysis of drug and device label differences
Postmarket modifications to fludeoxyglucose
F18 labeling that affect safety and
effectiveness when used with the device	Design verification and validation activities
Inaccurate therapeutic radiation dose delivery
due to intra- or inter-fractional changes of
fludeoxyglucose F18 biodistribution	Non-clinical performance testing
Clinical performance testing
Labeling
Incompatibility of the linear accelerator and
the PET scanner leading to machine failures
during treatment and treatment delay	Non-clinical performance testing
Electromagnetic compatibility (EMC) testing
Electrical safety testing
Software verification, validation, and hazard
analysis
Inadequate reader and device interpretation of
fludeoxyglucose F18 biodistribution for
determining treatment eligibility	Labeling
Clinical performance testing
Non-clinical performance testing
Training
Software verification, validation, and hazard
analysis
PET evaluation failure leading to treatment
delay and/or excess radiation exposure from
fludeoxyglucose F18	Non-clinical performance testing
Clinical performance testing
Labeling
Software verification, validation, and hazard
analysis
Inaccurate therapeutic radiation dose delivery
due to machine failure	Non-clinical performance testing
Labeling
Software verification, validation, and hazard
analysis
Uncertainty regarding external radiation dose
delivered to healthy tissue	Non-clinical performance testing
Software verification, validation, and hazard
analysis

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SPECIAL CONTROLS

In combination with the general controls of the FD&C Act, the fludeoxyglucose F18-guided radiation therapy system is subject to the following special controls:

• (1) An analysis must be provided of any effects on safety or effectiveness based on differences that exist in the use (i.e., concentration, rate of administration, route of administration; region, organ, or system of the body; or patient population) of fludeoxyglucose F18 with the device compared to the current approved drug labeling; and adequate justification, including support from clinical performance testing and labeling, must be provided that the differences do not adversely affect the safety and effectiveness of fludeoxyglucose F18 when used with the device.
• (2) Design verification and validation activities must include monitoring of changes to the labeling and formulation of fludeoxyglucose F18, and addressing such changes so that they do not adversely affect the safety and effectiveness of the device and fludeoxyglucose F18 when used with the device.
• (3) Clinical performance testing must demonstrate that the system performs as intended under anticipated conditions of use, including demonstrating: Adequate reader performance for distinguishing patients with eligible versus ineligible radiopharmaceutical biodistribution on imaging; reproducibility across fractions; and sufficient signal strength to meet system sensitivity requirements. Clinical performance testing under anticipated conditions of use must evaluate: Dose ranging for identification of lowest safe and adequate dose; and all adverse events.
• (4) Non-clinical performance testing under anticipated conditions of use must demonstrate:
  • (i) Compatibility of the linear accelerator and the tomography scanner;
  • (ii) Adequate PET imaging performance for patient selection in comparison with a legally marketed diagnostic scanner's output;
  • (iii) Adequacy of the chosen imaging metrics for inter- and intra-fractional treatment delivery; and
  • (iv) Dosimetric concurrence between delivered dose distributions and treatment plan, including comparison of delivery isolating difference between guidance on and off conditions.
• (5) Performance testing must demonstrate the electrical safety and electromagnetic compatibility (EMC) of anv electrical components.
• (6) Software verification, validation, and hazard analysis must be performed for any software components of the device. Software documentation must include a detailed description of the dose delivery tracking algorithms, including the dose calculation methods, treatment boundaries, treatment delivery fluence calculation methods, system latency for moving targets, interface for post-treatment review, limitations of the algorithm, and accompanying verification and validation testing to ensure device and algorithm functionality as informed by the software requirements and hazard analysis.
• (7) A training program must be included to ensure users can correctly interpret images to determine patient eligibility.
• (8) The labeling must include the following:

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• (i) A detailed description of the patient population included in clinical testing specifying age, primary cancer type, cancer stage, and target volume locations and sizes:
• (ii) A dedicated imaging agent section which includes a description of the use of fludeoxyglucose F18 with the device and a statement in the indications for use informing users where full prescribing information is available for fludeoxyglucose F18 in the current approved drug labeling and in the device labeling;
• (iii) Detailed instructions for use of fludeoxyglucose F18 with the device to guide radiation therapy: uptake time needed, time window to deliver treatment, physician review of pre-delivery safety checks, image interpretation, tissue targeted for fludeoxyglucose F18 uptake, pre-treatment image criteria to determine patient eligibility, and other differences compared to the current approved fludeoxyglucose F18 drug labeling;
• (iv) A detailed summary of the performance testing required under (3) and (4), including: test methods, dataset characteristics, and results;
• (v) A detailed description of the user workflow; and
• (vi) An instruction for users to plan for an alternative treatment if pre-treatment evaluation fails.

BENEFIT-RISK DETERMINATION

The probable risks of the device are based on nonclinical laboratory as well as data collected in a clinical study described above. The probable risks include: 1) Device-specific modifications of fludeoxyglucose F18 use compared to the current approved drug labeling that affect safety and effectiveness of fludeoxyglucose F18, 2) postmarket modifications to fludeoxyglucose F18 formulation or labeling that affect safety and effectiveness when used with the device. 3) inaccurate therapeutic radiation dose delivery due to intra- or inter-fractional changes of fludeoxyglucose F18 biodistribution, 4) incompatibility of the linear accelerator and the PET scanner leading to machine failures during treatment delay. 5) inadequate reader and device interpretation of fludeoxyglucose F18 biodistribution for determining treatment eligibility. 6) PET evaluation failure leading to treatment delay and/or excess radiation exposure from fludeoxyglucose F18, 7) Inaccurate therapeutic radiation dose delivery due to machine failure, and 8) uncertainty regarding external radiation dose delivered to healthy tissue.

The probable benefits of the device are also based on nonclinical laboratory as well as data collected in a clinical study as described above. The benefits of BgRT include real-time tracking of tumor motion, including physiological organ motion and patient position changes. Increased ability to track tumor motion in real time may allow for the reduction of target volumes, thus reducing radiation exposure to non-target tissue. Additionally, real time tracking of tumor motion may improve the accuracy of radiation delivery, which in turn can positively impact clinical outcomes. The pre-clinical performance testing shows that the device is able to deliver a dose to the prescribed target while minimizing dose to OAR. It has also shown that under specific conditions, the dose coverage with BgRT is more conformal than doing ITV based SBRT, and the treated tumor volume is smaller on average than the corresponding volume for SBRT. The clinical testing did not reveal any safety concerns with multiple injections of the radiotracer,

23

18F-FDG. The definitive magnitude and duration of benefit is uncertain, because no patients have been treated with the device.

Patient Perspectives

This submission did not include specific information on patient perspectives for this device.

Benefit/Risk Conclusion

In conclusion, given the available information above, for the following indication statement:

The RefleXion Medical Radiotherapy System is indicated for treatment planning and precise delivery of image-guided radiation therapy, stereotactic radiotherapy, or stereotactic radiosurgery for tumors or other targeted tissues anywhere in the body when radiation treatment is indicated, while minimizing the delivery of radiation to vital healthy tissue. The megavoltage X-ray radiation is delivered in a rotational, modulated, image-guided format in accordance with the physician approved plan.

The RefleXion Medical Radiotherapy System is also indicated for FDG-guided treatment which includes modeling, planning and precise delivery of FDG-guided radiation therapy, a type of Biology-guided Radiotherapy (BgRT), in five or fewer fractions for adults. It is indicated for tumor volumes in lung and bone subject to potential motion and positional uncertainty that have each been assessed with on-board PET/CT prior to delivery for adequate localization, sufficient FDG metabolic activity, local contrast and consistent biodistribution to meet the RMRS requirements, while minimizing the delivery of radiation to vital healthy tissue. BgRT involves the detection of signals from F18 during active beam delivery as a guide to deliver megavoltage X-ray radiotherapy in a rotational, modulated format in accordance with a physician approved treatment plan.

For complete fludeoxyglucose F18 prescribing information, refer both to the current medical imaging agent labeling and to this device labeling under "FDG Medical Imaging Agent Information".

The probable benefits outweigh the probable risks for the RefleXion Medical Radiotherapy System (RMRS). The device provides benefits and the risks can be mitigated by the use of general controls and the identified special controls.

CONCLUSION

The De Novo request for the RefleXion Medical Radiotherapy System (RMRS) is granted and the device is classified as follows:

Product Code: OVA Device Type: Fludeoxyglucose F18-guided radiation therapy system. Regulation Number: 21 CFR 892.5060 Class: II