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.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study proving the device meets them, based on the provided text, structured as requested:

Acceptance Criteria and Device Performance

1. Table of Acceptance Criteria and Reported Device Performance

The provided text details several performance tests and their acceptance criteria, primarily within the "SUMMARY OF NONCLINICAL/BENCH STUDIES" and "SUMMARY OF CLINICAL INFORMATION" sections. Due to the diverse nature of these tests, a single comprehensive table is challenging. Instead, I've organized them by the type of test (Bench Studies and Clinical Studies) and extracted the relevant acceptance criteria and results.

Bench Studies: Dosimetric Accuracy and Motion Tracking

Test	Purpose	Acceptance Criteria	Reported Device Performance
Moving target with 3-D respiratory and 3-D non-respiratory motion; organs at risk (OARs) independent motion	Demonstrate BgRT dose delivery accuracy to target(s) and measure dose to OARs with respiratory or non-respiratory continuous motion pattern; evaluate BgRT dose delivery accuracy to target and nearby normal tissues (OARs) for varying degrees of clinical motion patterns; compare with stereotactic body radiation therapy (SBRT) treatment delivery.	Coverage margin loss: Maximum of (CMP-CMD) in a given plane ≤ 3mm. Dosimetric coverage:* Dose at all points measured on film within the CTV ≥ 97% of prescription dose, but ≤ 130% of maximum planned dose. OAR point dose: Calibrated ion chamber measurement ≤ expected plan dose. OAR maximum dose: Maximum dose measured on radiochromic film inserted into OAR structure < maximum plan dose.	"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 - (positional uncertainty)	Demonstrate BgRT dose delivery accuracy to target(s) and OARs in the case of a single step shift of the target; evaluate effectiveness of BgRT treatment providing conformal dose to the target while sparing nearby normal tissues (OARs); evaluate BgRT dose delivery accuracy; compare with SBRT treatment delivery.	Same acceptance criteria as "Moving target with 3-D respiratory and 3-D non-respiratory 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."
Test clinical variations of targets (stationary)	Demonstrate 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, and homogeneous or heterogeneous backgrounds around the target.	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: 90% of comparison points (above 10% of prescription dose) within either 3% in dose or closer than 3mm in 3D space (DTA) to a point with the same dose. Overall Acceptance: PET Evaluation must pass AND either post-delivery DVH ≥ 95% points within bounds OR Gamma index > 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)	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 acceptance criteria as "Test clinical variations of targets (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	Demonstrate the benefit of BgRT in the same test setup by running with BgRT ON compared to BgRT OFF; evaluate BgRT dose delivery accuracy to target and measure dose to OAR with respiratory continuous motion pattern for the target; evaluate BgRT dose delivery accuracy to target and measure dose to OAR in the case of a single shift of the target.	Coverage margin loss: Maximum of (CMP-CMD) in a given plane ≤ 3mm. Dosimetric coverage:* Dose at all points measured on film within the CTV ≥ 97% of prescription dose, but ≤ 130% of maximum planned dose. OAR maximum dose: Maximum dose measured on radiochromic film over all valid dose points < (103% of bDVH maximum dose from 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	Determine accuracy of delivery with cases of lower target to background contrast.	Coverage margin loss: Maximum of (CMP-CMD) in a given plane ≤ 3mm. Dosimetric coverage:* Dose at all 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."

Clinical Study: Cohort I (RRFD and PET Imaging Performance)

Endpoint #	Description	Acceptance Criteria	Reported Device Performance
Primary Objective: RRFD	FDG Dose: Enables Activity Concentration necessary for BgRT functioning (i.e., 5 kBq/ml or higher).	All 6 evaluable cases met the threshold (> 5 kBq/ml), with values ranging from 7.46 to 21.05 kBq/ml.
Secondary Objective: BgRT PET Imaging-only Session Performance
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).	Not explicitly stated as a pass/fail criterion, but a high percentage indicates agreement.	Overall % agreement = 83.3% (5/6 eval. cases). 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).	Not explicitly stated as a pass/fail criterion, but high concordance is desirable.	Positive % agreement = 100% (6/6 eval. cases). 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.	Not explicitly stated as a pass/fail criterion, but a high percentage indicates acceptability.	67% (4/6 evaluable cases).
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.	90% of pixels meet 3 mm/3% deviation standard.	67% (4/6 evaluable cases). "100% (4/4) for all cases where an acceptable plan was created."

Clinical Study: Cohort II (BgRT Delivery Consistency and Workflow)

Endpoint #	Description	Acceptance Criteria	Reported Device Performance
Primary Objective: BgRT Dose Distribution Consistency
	Percent of radiotherapy fractions where the emulated BgRT dose distribution in silico was shown to be consistent with the approved BgRT treatment plan.	95% of DVH Delivered points for the BTZ and OAR fell within bounded DVH of the approved BgRT plan.	16/18 fractions (88.9%) met the 95% bDVH criterion. One lung case failed the first fraction (94.52%) and the last fraction "was not evaluable as the PET Evaluation did not pass." Another lung case resulted in a calculated volume reduction of -0.41%, indicating a slightly larger PTV than SBRT for that specific case. Overall, 88.9% success rate for this primary endpoint.
Secondary Objective: Workflow and Deliverability
1	Percent of fractions where there was concordance between the physical and digital phantoms of emulated BgRT delivery derived from human participant PET emissions.	90% of pixels meet 3 mm/3% deviation standard (gamma index).	100% (18/18)
2	Percent of cases where there was agreement between a SI and the AS for the BgRT PET PreScan localization decision (overall percent agreement).	Not explicitly stated as a pass/fail criterion, but a high percentage indicates 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).	Not explicitly stated as a pass/fail criterion, but high concordance is desirable.	Positive % agreement = 100% (7/7). Overall % agreement = 100%, Negative % agreement = N/A.
5a	Workflow: Percent of PET imaging sessions at RRFD that met the AC threshold for BgRT (5 kBq/mL).	5 kBq/mL.	100% (18/18 fractions)
5b	Workflow: Percent of PET imaging sessions which led to acceptable BgRT plans.	Acceptable BgRT plans based on user-defined coverage/avoidance goals.	100% (9/9 cases)
5c	Workflow: Percent of approved BgRT plans that went on to pass physics quality assurance.	90% of pixels meet 3 mm/3% deviation standard (gamma index).	100% (9/9 cases)
5d	Workflow: Percent of PET valuations on the day of fraction delivery that elicited a "Pass" signal.	"Pass" signal.	94% (17/18 fractions)

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

Bench Studies: The sample sizes for the bench studies are not explicitly stated in terms of a numerical count of "test sets" or cases. Instead, they describe the methodology (e.g., "large anthropomorphic phantom," "ArcCHECK Model") and the types of configurations tested (e.g., respiratory/non-respiratory motion, single step shifts, various target-to-background contrasts, edge cases, multi-target). The nature of these tests suggests a comprehensive exploration of the device's performance under simulated conditions.
- Provenance: In silico (simulated) and phantom studies. No specific country of origin is mentioned for the bench testing.
Clinical Studies:
- Cohort I: 8 patients were enrolled, with 6 having evaluable images for the secondary endpoints.
- Cohort II: 9 patients were enrolled (4 with bone tumors, 5 with lung tumors).
- Provenance: Prospective clinical trial conducted at two sites in the U.S.

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

Bench Studies: Ground truth for bench studies was established through the controlled and measurable nature of the phantom setups and physical dosimetric measurements (film, ion chambers). There's no mention of human experts establishing ground truth in terms of image review or clinical assessment for the bench tests.
Clinical Studies:
- Ground Truth for Planning and Treatment decisions:
  - Site Investigator (SI): Involved in the "localization decision" and "investigator assessment" for acceptable BgRT plans. Their specific qualifications are not detailed beyond being a "site investigator."
  - Agreement Standard (AS): Used in conjunction with the SI for localization decisions. The nature or composition of the AS is not explicitly defined (e.g., whether it's a consensus of experts, a reference standard from a central review).
  - Radiation Oncologist: Approved the detailed treatment plan and decided whether radiotherapy delivery with PET guidance was warranted based on metabolic characteristics (AC and NTS).
  - Medical Physicist or Dosimetrist: Developed the detailed treatment plan and conducted patient-specific quality assurance.
  - Clinical Expertise: Decisions on BgRT plan acceptability and patient positioning were made by clinical staff.
- "Cleared, third-party diagnostic PET/CT": This served as a comparative ground truth for evaluating PET imaging performance, implying that its established diagnostic accuracy serves as a reference.

4. Adjudication Method for the Test Set

Bench Studies: No specific "adjudication method" involving human experts is applicable, as the ground truth was based on physical measurements and controlled simulations.
Clinical Studies:
- For endpoint 1 (Cohort I) and 2 (Cohort II) (localization decisions), agreement was assessed between a "Site Investigator (SI)" and an "Agreement Standard (AS)." The method for establishing the "Agreement Standard" (e.g., consensus, expert panel) is not specified. It appears to be a direct comparison against a predefined reference, rather than a multi-reader, multi-case adjudication process.
- For endpoint 2 (Cohort I) and 3 (Cohort II) (concordance with diagnostic PET/CT), the comparison was against a "cleared, third-party diagnostic PET/CT," which serves as the established reference without explicit "adjudication" in the sense of multiple human readers resolving disagreements.
- No formal 2+1 or 3+1 adjudication method involving multiple independent expert readers is described for the clinical study data in the provided text. Decisions and assessments appear to be made by the "Investigator" or clinical staff.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, and what was the effect size of how much human readers improve with AI versus without AI assistance

No MRMC comparative effectiveness study involving human readers assisting with or being assisted by the RMRS (which incorporates AI/algorithmic guidance) is described in the provided text.
The clinical studies focus on the RMRS's performance against predefined criteria and existing diagnostic modalities, not on evaluating human reader improvement with AI assistance.

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

The "SUMMARY OF NONCLINICAL/BENCH STUDIES" section, particularly the detailed performance metrics for motion tracking, dosimetric coverage, and gamma index evaluations, represent the standalone algorithm performance in a controlled, simulated environment. These tests involved the device delivering radiation based on its algorithms and PET data, without human real-time intervention in the delivery process, and assessing the physical outcome.
In Cohort II, the "emulated BgRT dose distribution in silico" and the concordance between "physical and digital phantoms of emulated BgRT delivery" also reflect the standalone performance of the algorithm in generating and confirming deliverable fluence based on human patient PET emissions. While human input is involved in initial planning and approval, the core evaluation of dose delivery consistency and accuracy is algorithmic.

7. The Type of Ground Truth Used

Bench Studies: Ground truth was established through physical measurements (e.g., film dosimetry, ion chamber measurements) in highly controlled phantom environments, along with the precise knowledge of programmed motion and simulated targets. This constitutes a manufactured or precisely controlled ground truth.
Clinical Studies:
- Comparative Reference: For PET imaging performance, a "cleared, third-party diagnostic PET/CT" served as a comparative ground truth for localization decisions and "plan proceed" decisions.
- Clinical Assessment/Investigator Opinion: For whether RefleXion PET data could be used to generate an "acceptable BgRT plan," the ground truth was based on Investigator assessment.
- Dosimetric QA Standards: For the achievement of intended dose distribution and plan quality assurance, the ground truth was defined by established radiotherapeutic quality assurance standards (e.g., gamma index meeting 3 mm/3% deviation standard, DVH metrics).
- In Silico Emulation: For the primary endpoint in Cohort II, the consistency of the emulated dose distribution was compared against the "approved BgRT plan." This is a form of design-specific ground truth derived from the planning system's output.

8. The Sample Size for the Training Set

The provided text describes performance testing and clinical studies for validation. It does not mention a separate training set or its sample size for the development of any AI/algorithm components within the RMRS. The information focuses solely on the validation data. It's possible the device's algorithms were developed internally or on proprietary datasets not detailed in this submission summary.

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

Since no training set and its use in algorithm development are explicitly described, there is no information provided on how its ground truth was established.

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.

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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 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.

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

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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.

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).

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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

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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 Metricsand AcceptanceCriteria	Results
Moving targetwith 3-Drespiratory and3-D non-respiratorymotion; organsat risk (OARs)independentmotion	To demonstrate theBgRT dose deliveryaccuracy to target(s)and measure dose toOARs with respiratoryor non-respiratorycontinuous motionpattern:• BgRT dose deliveryaccuracy to targetand nearby normaltissues (OARs)• BgRT dose deliveryaccuracy for varyingdegrees of clinicalmotion patterns• Comparison withstereotactic bodyradiation therapy(SBRT) treatmentdelivery	Tests were performedwith a largeanthropomorphicphantom. Thebackground consistedof water with FDG tosimulate an FDG-activebackground. Two armswere included thatcould be programmedwith distinct motionpatterns. Inserts ofvarying shape/size wereinjected with FDG tosimulate targets orOARs. The shapesincluded sphere, C-shape, and ovoid. TheC-shape and sphereOARs were used forrespiratory motion tests,and the ovoid was usedfor the non-respiratorymotion test.	Coverage margin loss -The maximum of(CMP-CMD* in agiven plane) for allplanes in 3D space. Theacceptance criterion forcoverage margin loss is≤ 3mm.Dosimetric coverage -Dose at all the pointsmeasured on filmwithin the CTV ≥ 97%of prescription dose,but ≤ 130% ofmaximum planneddose.For the OAR, twomeasurements weremade. A point dosemeasurement was madeby a calibrated ionchamber and wasrequired to be less thanor equal to the expectedplan dose as aquantitative dose check.In addition, themaximum dosemeasured on theradiochromic filminserted into the OARstructure was requiredto be less than themaximum plan dose asa qualitative dosecheck.	Both dosimetriccoverage criteria aswell as OAR dosecriteria were met for allBgRT test cases.Under the same testcircumstances, SBRTplans with an ITVapproach for the targetwere not able tosuccessfully meet thesame criteria as theBgRT plans.
Target or OARwith a singlestep shift -	To demonstrate theBgRT dose deliveryaccuracy to target(s)	Same methodology asdescribed above. Aspecific OAR shape	Same acceptancecriteria as describedabove.	Both dosimetriccoverage criteria aswell as OAR dose
(positionaluncertainty)	OARs in the case of asingle step shift of thetarget:• Effectiveness ofBgRT treatmentproviding conformaldose to the targetwhile sparing nearbynormal tissues(OARs)• BgRT dose deliveryaccuracy• Comparison withSBRT treatmentdelivery	was not utilized for thistest.	criteria were met for allBgRT test cases.Under the same testcircumstances, SBRTplans with an ITVapproach for the targetwere not able tosuccessfully meet thesame criteria as theBgRT plans.
Test clinicalvariations oftargets(stationary)	To demonstrate theBgRT dose deliveryaccuracy for variousclinical situations:• Various target-to-background (T:B)contrast• Different FDGbiodistributionpatterns betweenplanning anddelivery whilekeeping the sameanatomic shape ofthe target• Test homogenous orheterogenousbackgrounds aroundthe target	The phantom used inthe stationary tests wasthe ArcCHECK Model(b)(4)	PET evaluation results(AC/NTS/bDVH).Bounded DVH – 95%of points in thecalculated dose DVHsof all static structuresmust be within thebounds of the bDVHfrom the treatment plan.Gamma Index - Thismethod compares theplan dose extrapolatedto all points in spacerepresented by the(calibrated) detectordiodes. The acceptancecriteria chosen for thesetests required that 90%of the comparisonpoints (that were above10% of the prescriptiondose) were within either3% in dose or closerthan 3mm in 3D space(DTA or distance toagreement) to a pointwith the same dose.Acceptance criteriarequires both the PETEvaluation to pass andeither post-deliveryDVH to have ≥ 95% ofthe points fall withinthe bounds of thetreatment plan and/orthe Gamma index to beabove 90%	For all tests where theacceptance criteriarequired both the PETevaluation to pass andeither the post-treatment doseevaluation against theplan and/or the Gammaindex to pass met thedose accuracy criteria.For cases where therewas a significantchange inbiodistribution in thetarget, low contrastbetween the target andbackground, or achange in thebackground signal, thePET evaluation did notpass, and the resultingdose accuracy showedmixed results.
Tests evaluatingspecial edgecases(stationary)	To demonstraterobustness of the BgRTsystem underchallenging situations:• Variations betweenplanning anddelivery such aschanges in PETbiodistributionpatterns• PET-avid OAR in theBTZ prior to delivery• Dose deliveryaccuracy to target inthe presence ofnearby PET-avidOAR.• PET Evaluation stepchallenge with largechanges betweenplanning anddelivery	Same methodology asdescribed above withstationary tests.	Same acceptancecriteria as describedabove with stationarytests.	For cases where therewas a significantchange inbiodistribution betweenplanning and delivery,or a situation when anFDG-avid target movesinto the BTZ, the PETevaluation did not pass.
BgRT ON/OFFwith MotionON/OFF	To demonstrate thebenefit of BgRT in thesame test setup byrunning with BgRT ONcompared to BgRTOFF.• BgRT dose deliveryaccuracy to targetand measure dose toOAR withrespiratorycontinuous motionpattern for the target• BgRT dose deliveryaccuracy to targetand measure dose toOAR in the case of asingle shift of thetarget	Same phantom as usedwith the motion testsdescribed above. TheC-shape was used forrespiratory motion tests,and the sphere was usedfor the non-respiratorymotion test.	Coverage margin loss -The maximum of(CMP-CMD* in agiven plane) for allplanes in 3D space. Theacceptance criterion forcoverage margin loss is≤ 3mm.Dosimetric coverage -Dose at all the pointsmeasured on filmwithin the CTV ≥ 97%of prescription dose,but ≤ 130% ofmaximum planneddose.For nearby OARs, themaximum dose will bemeasured usingradiochromic film overall valid dose pointsand the acceptancecriteria is that themaximum dosemeasured on the filmmust be below a valuethat is 3% higher thanthe bDVH maximumdose as calculated bythe plan.	BgRT ON Motion ON -The tracked dosedelivery wassuccessfully providedwhere the CTV wasfully covered (100%) inall cases. In cases forwhich the PETevaluation did not pass,some degradation tomargin loss wasobserved.BgRT OFF Motion ON- In all cases doseaccuracy failed thecriteria. The CTV dosecoverage was less than100% and margin losshigher than 3.0mm.BgRT ON Motion OFF- All test cases met thedose accuracy criteria.BgRT OFF MotionOFF - All test casesmet the dose accuracycriteria.
Multi-targettesting	To determine accuracyof delivery with casesof lower target tobackground contrast	Same methodology asmotion testing.	Coverage margin loss -The maximum of(CMP-CMD* in agiven plane) for allplanes in 3D space. Theacceptance criterion forcoverage margin loss is≤3mm.Dosimetric coverage -Dose at all the pointsmeasured on filmwithin the CTV ≥ 97%of prescription dose,but ≤ 130% ofmaximum planneddose	For all 3-target, movingtests, including withreduced target:background for thesecond and thirdtargets, all dosimetriccriteria (CTV dosecoverage and MarginLoss) were met.

PERFORMANCE TESTING - BENCH

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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

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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.
  - 1. 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.
  - 1. 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.
  - 1. 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.

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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 ECOGperformance 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)	ActivityConcentration(kBq/ml)	Met the Thresholdfor 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.

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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 agreementbetween a SI and AS for the BgRT PET imaging-only session localization decision (overallpercent agreement).	Overall % agreement = 83.3% (5/6)Positive % agreement = 83.3%Negative % agreement = N/A
2	Percent of cases where there was concordance ofthe positive “plan proceed” decision between theBgRT imaging-only session PET and a cleared,third-party diagnostic PET/CT (positive percentagreement).	Positive % agreement = 100% (6/6)Overall % agreement = 83.3%*Negative % agreement = 0
3	Percent of cases where RefleXion PET datacould be used to generate an acceptable BgRTplan such that relevant dosimetric parameters forthe target and the nearby normal anatomy weremet based on Investigator assessment.	67% (4/6)
4	Percent of cases where the intended dosedistribution of the BgRT plan was achieved in aphysical phantom, defined as meeting a standardgamma index for external beam radiotherapyquality assurance, i.e., whether 90% of pixelsmeet the 3 mm/3% deviation standard.	67% (4/6)100% (4/4) for all cases where anacceptable 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 ClassPreferred 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.
  - 1. 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.
  - 1. 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.
  - 1. 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.
  - 1. 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:

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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
  - 1. 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

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		Hispanic or Latino: 20%(1)	Hispanic or Latino: 11.2%(1)
Race	Black or AfricanAmerican: 25% (1)White: 75% (3)	Black or AfricanAmerican: 40% (2)White: 40% (2)American Indian orAlaskan Native: 20% (1)	Black or AfricanAmerican: 33.3% (3)White: 55.6% (5)American Indian orAlaskan Native: 11.1% (1)
Baseline ECOGperformancestatus	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	EmulatedDeliverybDVH% (>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
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#	Description	Result
1	Percent of fractions where there was concordancebetween the physical and digital phantoms of emulatedBgRT delivery derived from human participant PETemissions. Concordance was defined as a standardgamma index with a goal that 90% of pixels met the 3mm/3% deviation standard.	100% (18/18)
2	Percent of cases where there was agreement between anSI and the AS for the BgRT PET PreScan localizationdecision (overall percent agreement).	Overall % agreement = 72.2%(13/18)Positive % agreement = 80%Negative % agreement = 33%
3	Percent of cases where there was concordance of apositive localization decision between the short-durationPET 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 toxicityrates of bladder and bone marrow.	The reported events weredocumented by the investigatoras not being related to the studydevice or FDG injection. Noneresulted in discontinuation of thesubject in the study.
Sa	Workflow: Percent of PET imaging sessions at RRFDthat met the AC threshold for BgRT (5 kBq/mL)	100% (18/18 fractions)
5b	Workflow: Percent of PET imaging sessions which ledto acceptable BgRT plans.	100% (9/9 cases)
5c	Workflow: Percent of approved BgRT plans that wenton to pass physics quality assurance.	100% (9/9 cases)
રવ	Workflow: Percent of PET valuations on the day offraction 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 tumorlocation	BgRT (PTV)(cc)	SBRT (PTV orIPTV) (cc)	AbsoluteVolumeReductionwith BgRT(cc)	% VolumeReductionwith 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	Targettumorlocation	Lateral(mm)	Ant-Post(mm)	Sup-Inf(mm)	CalculatedTotal 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 offludeoxyglucose F18 use compared to thecurrent approved drug label that affect safetyand effectiveness of fludeoxyglucose F18	Clinical performance testingLabelingAnalysis of drug and device label differences
Postmarket modifications to fludeoxyglucoseF18 labeling that affect safety andeffectiveness when used with the device	Design verification and validation activities
Inaccurate therapeutic radiation dose deliverydue to intra- or inter-fractional changes offludeoxyglucose F18 biodistribution	Non-clinical performance testingClinical performance testingLabeling
Incompatibility of the linear accelerator andthe PET scanner leading to machine failuresduring treatment and treatment delay	Non-clinical performance testingElectromagnetic compatibility (EMC) testingElectrical safety testingSoftware verification, validation, and hazardanalysis
Inadequate reader and device interpretation offludeoxyglucose F18 biodistribution fordetermining treatment eligibility	LabelingClinical performance testingNon-clinical performance testingTrainingSoftware verification, validation, and hazardanalysis
PET evaluation failure leading to treatmentdelay and/or excess radiation exposure fromfludeoxyglucose F18	Non-clinical performance testingClinical performance testingLabelingSoftware verification, validation, and hazardanalysis
Inaccurate therapeutic radiation dose deliverydue to machine failure	Non-clinical performance testingLabelingSoftware verification, validation, and hazardanalysis
Uncertainty regarding external radiation dosedelivered to healthy tissue	Non-clinical performance testingSoftware verification, validation, and hazardanalysis

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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,

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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.

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

Regulation Number and Section

N/A