(362 days)
The BrachyGel Vaginal Hydrogel Packing System is a single-use, non-sterile, disposable, non-powered positioning device that delivers self-expanding hydrogel that forms and expands within the vaginal cavity. The purpose of this device is to displace the vaginal wall and adjacent pelvic tissues during radiation therapy planning and delivery, to reduce dose to adjacent tissues by attenuation of radiation dose, and to stabilize radiation treatment equipment during radiation therapy planning and delivery. The placement of the hydrogel device requires a physician or physician directed healthcare professional, and is performed as a separate procedure outside of brachytherapy applicator insertion. computed tomography and/or magnetic resonance imaging exam, radiation treatment planning and radiation treatment delivery. This device is not intended to be inserted into the uterine cavity or rectum. This device is intended to be in place temporarily and removed after less than 24 hours.
The device, BrachyGel Vaginal Hydrogel Packing System (BVHPS), is intended for patients receiving brachytherapy for gynecological cancers. The BVHPS works by displacing the rectum and bladder, providing radiation attenuation and stabilizing the brachytherapy applicator. The device contains components for the preparation of a polyethylene glycol (PEG) based polymer hydrogel and hydrogel delivery system (Figure 1). After the bag is placed into the vaginal space, the hydrogel precursors are injected into the therapy bag and the hydrogel forms in situ, causing the bag to expand and displace nearby tissue and stabilize the brachytherapy applicator. The bag containing the hydrogel is later removed after the brachytherapy treatment delivery is complete. The physician may instill saline via the device's saline port to soften the hydrogel for easier extraction of the therapy bag. The hydrogel is not bioresorbable.
The provided text describes the BrachyGel Vaginal Hydrogel Packing System and its clinical evaluation for De Novo classification. However, it does not describe an AI medical device or a study proving that an AI device meets acceptance criteria. The information focuses on the physical device's performance, safety, and equivalence to standard care in a clinical setting.
Therefore, I cannot fulfill the request as it pertains to an AI medical device and its acceptance criteria, as the input document describes a physical medical device (a vaginal hydrogel packing system) and its associated clinical study, not an AI algorithm or its performance. The concept of "acceptance criteria for an AI device" as typically understood (e.g., sensitivity, specificity, AUC) is not applicable to the BrachyGel Vaginal Hydrogel Packing System.
To answer your prompt fully, I would need a document describing an AI medical device and its performance study.
If we interpret "acceptance criteria" broadly to refer to the device's performance as demonstrated in the provided text, and "study" to refer to the clinical trial conducted for the BrachyGel device, I can construct a response based on the available information, but it will not involve AI-specific metrics.
Assuming the request is a misinterpretation of the provided text, and the intent is to describe the acceptance criteria and study for the BrachyGel Vaginal Hydrogel Packing System as described, here is the information:
Acceptance Criteria and Study Proving Device Meets Acceptance Criteria for BrachyGel Vaginal Hydrogel Packing System
The provided document describes the BrachyGel Vaginal Hydrogel Packing System, a physical medical device, not an AI device. Therefore, the acceptance criteria and study detailed below pertain to the performance and safety of this physical device in a clinical setting, primarily focusing on its non-inferiority to standard care and other performance characteristics.
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria for this device are not explicitly laid out in a quantifiable table as one might see for an AI algorithm (e.g., sensitivity, specificity thresholds). Instead, they are defined by the success of the clinical study in demonstrating non-inferiority in dosimetric results, acceptable safety profile, and favorable user experience. The "acceptance criteria" here implicitly refer to demonstrating the device's intended performance and safety profile, as outlined in the "Special Controls" section.
| Acceptance Criteria (Implied from Study Objectives and Special Controls) | Reported Device Performance (Clinical Study Results) |
|---|---|
| Clinical Performance: | |
| - Radiation dose to adjacent organs at risk (D2cc for rectum/bladder) | - Bladder D2cc: Mean difference (Gauze - BVHPS) was 0.07 Gy. Percent of HR-CTV D90 difference (Gauze - BVHPS) was -0.57%. No clinically meaningful differences. |
| - Rectal D2cc: Mean difference (Gauze - BVHPS) was -0.17 Gy. Percent of HR-CTV D90 difference (Gauze - BVHPS) was -4.90%. No clinically meaningful differences. | |
| - Device stability | - Investigator observations noted the BVHPS device remained solid and in appropriate position throughout the treatment planning and delivery process. Also addressed by bench testing (Table 1: "Stability of the Applicator" - Pass). |
| - Ability to deploy, expand, and remove the device | - Placement and removal demonstrated in all studied cases. Physician survey showed BVHPS with significantly higher "extremely easy" (21.1%) and "somewhat easy" (66.7%) scores compared to gauze (0% "extremely easy", 72.4% "somewhat easy"). Patient surveys suggested less discomfort during placement and removal with BVHPS (23.3% "none" vs. 7.4% for gauze). Bench testing ("Bag Burst Strength - Burst Volume" and "Mechanical and Dimensional Testing of Connectors") passed, showing adequate function. |
| - Patient comfort | - Patient survey: Less discomfort during placement and removal for BVHPS (23.3% none, 36.7% mild) compared to standard packing (7.4% none, 44.4% mild). Overall discomfort: BVHPS showed slightly higher "none" (6.7% vs 3.7%) and "mild" (46.7% vs 40.7%) discomfort. |
| Safety Profile (Adverse Events) | - No increase in serious adverse events compared to the standard packing control group. Three adverse events were "definitely" or "possibly" related to BVHPS: Grade 2 Vaginal Pain, Grade 1 Vaginal Hemorrhage, and another Grade 2 Vaginal Pain, all resolved without sequelae. |
| Imaging Clarity | - Mixed results. Physicians reported fewer "very clear" ratings for BVHPS (0%) compared to gauze (23.1%), but more "clear" ratings (60.5% vs 43.6%). Physicists gave more "excellent" (44.7% vs 25.6%) and "good" (42.1% vs 53.9%) ratings for BVHPS completeness, but fewer "very clear" ratings for imaging clarity (31.6% vs 38.5%). |
| Non-clinical Performance (Bench Testing): | |
| - Effect of therapeutic radiation levels on device integrity | - "Hydrogel Raw Material Characterization Before and After Irradiation": Pass. No evidence of altered rheological properties. |
| - Bioburden testing | - Passed predetermined acceptance criteria. |
| - Structural integrity of container (tensile, leakage, burst strength) | - "Bag Integrity - Leak Test": Pass. "Bag Burst Strength - Burst Volume": Pass. Test methods like ASTM F1886/F1886M-16 and ASTM F88/F88M-21 (for seal strength) were used for shelf life and package integrity, implying these aspects were acceptable. |
| - Space creation and maintenance | - Addressed by "Stability of the Applicator" bench test (Pass) and clinical observations that the device displaced tissue and stabilized the applicator. |
| - Biocompatibility | - All tested endpoints (Cytotoxicity, Sensitization, Irritation, Acute systemic toxicity, Materials mediated pyrogenicity) passed according to ISO 10993. |
| - Shelf life and functionality | - Established at 6 months, supported by package and functional testing. |
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size: The clinical study accrued a total of 20 evaluable patients out of a planned enrollment of 40. Twenty-one patients were initially enrolled, but one was not treated due to disease progression. This sample size was deemed sufficient to judge comparability of D2cc between the two methods, although not large enough to statistically determine non-inferiority as initially powered.
- Data Provenance: The study was conducted at a single site, the University of Virginia. The data is prospective, collected during a randomized clinical trial comparing the BrachyGel device to standard vaginal packing (gauze) in patients receiving HDR brachytherapy for cervical cancer. The country of origin is USA.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
For this physical device, "ground truth" primarily refers to the actual dosimetric measurements and clinical observations.
- Dosimetric Measurements: These were derived from CT scans obtained after applicator placement and vaginal packing for brachytherapy planning. The "experts" involved are the radiation oncologists and physicists who designed and administered the brachytherapy, calculated the doses (D2cc, D90), and evaluated the imaging and packing completeness. While the exact number of individuals involved in the dosimetric calculations and image interpretations isn't specified, the text states that "a total of 5 physicians at the University of Virginia performed BVHPS insertion and removal." The study also involved evaluation by "physicians" and "physicists" (plural). Their qualifications are implied by their roles in a university medical center and their ability to conduct a clinical trial for FDA submission.
- Clinical Observations/Surveys: Five physicians performed insertions/removals and completed surveys. The "physicists" involved also provided evaluations through surveys. The "experts" here are those physicians and physicists directly involved in the patient care and study assessments. No external or blinded panel of experts was described for establishing a "ground truth" beyond the routine clinical workflow and study assessments.
4. Adjudication Method for the Test Set
No explicit adjudication method (e.g., 2+1, 3+1) for resolving disagreements in "ground truth" or primary endpoint measurements is described. The dosimetric values (D2cc) are quantitative measurements derived from treatment plans. Physician and physicist evaluations (e.g., completeness, imaging clarity) were collected via surveys, and while collective results are presented, an adjudication process for individual discrepancies is not mentioned.
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 vs. Without AI Assistance
This question is not applicable. The study was a randomized non-inferiority clinical study evaluating a physical medical device (BrachyGel) against a standard of care (gauze packing). It did not involve AI assistance, human readers interpreting images with or without AI, or an MRMC study design for an AI algorithm. Therefore, there is no effect size related to AI assistance.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
This question is not applicable as the device is a physical hydrogel packing system, not an AI algorithm.
7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, etc.)
The "ground truth" for the primary endpoint (dosimetric results, D2cc for bladder and rectum) was based on quantitative dosimetric calculations from CT imaging, which are standard in brachytherapy planning. These are essentially "outcomes data" in terms of radiation delivery to organs at risk.
For secondary and exploratory endpoints:
- Adverse Events: Clinical documentation based on clinical observation and patient self-report, graded by CTC AE v5 criteria.
- Patient Discomfort: Patient-reported outcomes via surveys.
- Physician/Physicist Evaluations: Clinician-reported outcomes via surveys, based on their physical examination and interpretation of CT images.
8. The Sample Size for the Training Set
This question is not applicable as the device is a physical medical device and does not involve a "training set" in the context of machine learning. The clinical trial serves as the primary dataset for regulatory evaluation.
9. How the Ground Truth for the Training Set Was Established
This question is not applicable, as there is no "training set" for an AI algorithm provided in the context of this physical device.
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DE NOVO CLASSIFICATION REQUEST FOR BRACHYGEL VAGINAL HYDROGEL PACKING SYSTEM
REGULATORY INFORMATION
FDA identifies this generic type of device as:
Vaginal hydrogel packing system. A vaginal hydrogel packing system is a nonpowered positioning device composed of a flexible container filled with a hydrogel. The device is intended to reduce the radiation dose delivered to adjacent pelvic organs by temporarily displacing the vaginal wall and adjacent pelvic tissues during radiation therapy treatment planning and delivery.
NEW REGULATION NUMBER: 21 CFR 892.5735
CLASSIFICATION: Class II
PRODUCT CODE: QXR
BACKGROUND
DEVICE NAME: BrachyGel Vaginal Hydrogel Packing System
SUBMISSION NUMBER: DEN220052
DATE DE NOVO RECEIVED: August 26, 2022
SPONSOR INFORMATION:
BrachyFoam, Inc. d/b/a Advaray 722 Preston Ave. Suite 108 Charlottesville, VA 22093
INDICATIONS FOR USE
The BrachyGel Vaginal Hydrogel Packing System is indicated as follows:
The BrachyGel Vaginal Hydrogel Packing System is a single-use, non-sterile, disposable, non-powered positioning device that delivers self-expanding hydrogel that forms and expands within the vaginal cavity. The purpose of this device is to displace the vaginal wall and adjacent pelvic tissues during radiation therapy planning and delivery, to reduce dose to adjacent tissues by attenuation of radiation dose, and to stabilize radiation treatment equipment during radiation therapy planning and delivery. The placement of the hydrogel device requires a physician or physician directed healthcare professional, and is performed as a separate procedure outside of brachytherapy applicator insertion. computed tomography and/or magnetic resonance imaging exam, radiation treatment
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planning and radiation treatment delivery. This device is not intended to be inserted into the uterine cavity or rectum. This device is intended to be in place temporarily and removed after less than 24 hours.
LIMITATIONS
The sale, distribution, and use of the BrachyGel Vaginal Hydrogel Packing System are restricted to prescription use in accordance with 21 CFR 801.109.
The device is intended only for use in the vaginal cavity; it is not intended to be inserted into the uterine cavity or rectum.
The device is intended to be in place temporarily and removed within 24 hours.
The device is non-sterile, single-use, and cannot be reprocessed.
The clinical study was unblinded; therefore, clinicians and patients participating in the study would know when the device or standard of care packing was used.
PLEASE REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.
DEVICE DESCRIPTION
The device, BrachyGel Vaginal Hydrogel Packing System (BVHPS), is intended for patients receiving brachytherapy for gynecological cancers. The BVHPS works by displacing the rectum and bladder, providing radiation attenuation and stabilizing the brachytherapy applicator. The device contains components for the preparation of a polyethylene glycol (PEG) based polymer hydrogel and hydrogel delivery system (Figure 1). After the bag is placed into the vaginal space, the hydrogel precursors are injected into the therapy bag and the hydrogel forms in situ, causing the bag to expand and displace nearby tissue and stabilize the brachytherapy applicator. The bag containing the hydrogel is later removed after the brachytherapy treatment delivery is complete. The physician may instill saline via the device's saline port to soften the hydrogel for easier extraction of the therapy bag. The hydrogel is not bioresorbable.
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Image /page/2/Picture/0 description: The image shows a medical kit with various components labeled with numbers and text. Component 1 is labeled as 'Shaft', and it is connected to a 'Stopcock' and 'Saline Flush Port, Plastic Filament'. Component 2 is a 'Y-connector', while component 3 is a syringe-like device. Component 4 consists of 'Hydrogel Syringes' and a 'Therapy Bag'.
Figure 1. BrachyGel Vaginal Hydrogel Packing System with components identified (1: Dual Lumen Catheter Assembly, 2: Flexible Y Connector, 3: Dual Syringe Assembly, 4: Package Card)
Device Components and Specifications
Each BVHPS includes the following components:
- · Prefilled THIOCURE Syringe (Syringe 1)
- Contains a solution of THIOCURE ETTMP 1300, water, and sodium bicarbonate. O
- · Prefilled PEDGA Syringe (Syringe 2)
- o Contains a solution of Poly(ethylene glycol) diacrylate (PEDGA) average Mn 700 and water.
- · Dual Syringe Holder
- · Dual Syringe Clip
- · Flexible Y Connector
- · Catheter Assembly with Therapy Bag
- The therapy bag is 2.2 MIL in thickness and 4.585 in x 2.75 in (LxW). The intended fill O volume is 50ml.
Principle of Operation
The BVHPS is deployed in three steps: insertion, delivery of hydrogel, and removal. During insertion, the BVHPS is placed to the desired depth within the vagina, anterior or posterior to the brachytherapy treatment applicators. If desired, a second device may be inserted to the desired depth anterior or posterior to the brachytherapy treatment applicators. The Y connector tubing is attached to the device shaft, and the hydrogel reagents are injected continually. The chemical reaction between the polymer solutions occurs within the reaction bag itself. The maximum time between injection of the polymer solutions and gelation is one minute. The expansion of the bag upon filling displaces adjacent tissue, providing radiation attenuation, and stabilizing the brachytherapy applicator during a brachytherapy treatment fraction. Gel delivery can be performed sequentially if two BVPHs are placed.
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Once radiation treatment is complete, the physician may instill saline solution through the saline port in order to soften the hydrogel for easier removal. Each BVHPS is then removed from the vagina.
In the event that the hydrogel reaction does not occur as intended, the physician should be able to detect the event by noticing the lack of expansion to fit the vaginal cavity and stabilize the applicator, or by identifying suboptimal packing on treatment planning CT or MRI images obtained after insertion of the BVHPS. If a device fails, the physician should remove the BVHPS and repeat the packing placement procedure with another BVHPS kit or alternative form of packing.
SUMMARY OF NONCLINICAL/BENCH STUDIES
BIOCOMPATIBILITY/MATERIALS
Biocompatibility testing was conducted on the final, finished device. The test article consisted of the therapy bag and solidified hydrogel material. Biocompatibility was evaluated according to ISO 10993-1:2009 and the FDA Guidance, "Use of International Standard ISO 10993, Biological Evaluation of Medical Devices – Part 1: Evaluation Testing". The results showed that the device met acceptance criteria according to ISO 10993. A summary of the results is below.
The following biocompatibility endpoints were evaluated with testing:
- Cytotoxicity
- Sensitization
- Irritation ●
- Acute systemic toxicity ●
- Materials mediated pyrogenicity ●
The results of these evaluations support the biocompatibility of the BVHPS.
SHELF LIFE/STERILITY
The device is provided non-sterile and is single-use only.
Bioburden Testing
Bioburden testing was performed on the patient-contacting component (therapy bag) of the device as per USP <61>, USP <62>, and USP <1111>. The tests passed the predetermined acceptance criteria and were found acceptable.
Shelf Life
The BVHPS is a non-sterile, single use device. The shelf-life has been established at 6 months. To support the 6-month shelf life, package testing and functional testing were performed. Package testing consisted of the following:
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- Visual Inspection (ASTM F1886/F1886M-16, Standard Test Method for . Determining Integrity of Seals for Flexible Packaging by Visual Inspection)
- . Seal strength (ASTM F88/F88M-21, Standard Test Method for Seal Strength of Flexible Barrier Materials)
- Simulated distribution testing in accordance with ASTM D4169-16. .
MAGNETIC RESONANCE (MR) COMPATIBILITY
The device is composed of materials that are electrically nonconductive, nonmetallic, and nonmagnetic. The device is considered MR Safe.
PERFORMANCE TESTING - BENCH
Bench testing was conducted to demonstrate that the BVHPS performs as expected under the anticipated conditions of use. The following bench testing was conducted to demonstrate the device performance characteristics:
| Test | Purpose | Method | PerformanceMetrics andAcceptanceCriteria | Results |
|---|---|---|---|---|
| Hydrogel RawMaterialCharacterizationBefore and AfterIrradiation | To determine if thehydrogel materialsmaintained theirchemical andphysical propertiesafter irradiation | (b) (4) | (b) (4) | Pass. There is noevidence to showthat the gel'srheologicalproperties aredifferent before andafter irradiation. |
| MaterialCharacterization ofthe hydrogels atstorage timepoints of(b) (4) | To determinestorage conditions ofthe gel precursors | Samples were agedat 2 - 8°C, and thentested for gel time.Samples were storedfor (b) (4) | At all timepoints, allsamples stored at 2 –8°C passed. Thelabeling states thatthe device should bestored at conditions2 – 8°C. | |
| Exothermic Testingof HydrogelReaction | To ensure that thedevice does notcause adversereactions fromincreased heat by thehydrogel reaction | (b) (4) | The acceptancecriteria wereobservational, sothere were nospecific pass/failcriteria. The resultsindicated theaverage temperatureincrease was lessthan 5°C and did not | |
| (b) (4) | This | |||
| RadiationAttenuation | To determine theradiation doseattenuationproperties of thedevice materials | (b) (4) | is acceptable.Pass. (b) (4)(b) (4) | |
| ComputedTomography (CT)Imaging | To determine if thedevice is visible on aCT image | Pass. (b) (4)(b) (4) | ||
| Stability of theApplicator | To determine theability of the deviceto stabilize theapplicator | Pass. (b) (4)(b) (4) | ||
| Bag Integrity - LeakTest | To demonstrate thatthere is no leachingof the hydrogel outof the vaginal fillbag | Pass. (b) (4)(b) (4) | ||
| Bag Burst Strength -Burst Volume | To determinemaximum fillvolume of the bag | Pass. (b) (4)(b) (4) | ||
| Mechanical andDimensional Testingof Connectors | To ensure that thedevice joints andconnectors functionadequately | (b) (4) | (b) (4) | Pass. (b) (4)(b) (4) |
Table 1. Performance testing completed for BrachyGel Vaginal Hydrogel Packing System
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SUMMARY OF CLINICAL INFORMATION
The study aimed to determine whether the device is non-inferior to standard vaginal packing (gauze) in dosimetric results for the rectum and bladder, as well as to determine the differences in participant discomfort, CT imaging clarity of packing, physician/physicist use experience, and impact of the device on complication rates and adverse events. The study evaluated the clinical performance of the device during high dose rate (HDR) brachytherapy for cervical cancer.
| Clinical Study Title | A Randomized, Non-Inferiority Study of a Hydrogel Packing System Compared toStandard of Care Packing During Image-Guided High-Dose Rate BrachytherapyBoost for Cervical Cancer | ||
|---|---|---|---|
| Objectives and Endpoints | Primary objective: To determine ifBVHPS is non-inferior to standardmethod vaginal packing (standard) indose thresholds for the rectum and thebladder. | Primary Endpoint: The dose to thehottest 2 cc (D2cc) (in Gy) for therectum and the bladder in periods 1 and2 (e.g., fractions 2 and 3). | |
| Secondary Objectives:1) To estimate the difference inthe safety profile of BVHPScompared to standard vaginalpacking. | Secondary Endpoints:1) Frequency, intensity, andduration of adverse events inperiods 1 through 4 (e.g.,fractions 2 through 5). |
Table 2. Summary of Clinical Study Objectives and Endpoints
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| 2) | To estimate period effects indosimetry thresholds (D0.1cc,D1cc, D2cc) betweenBrachyGel and standard vaginalpacking for the rectum and thebladder. | 2) | The dose to the hottest 0.1 cc(D0.1cc), 1cc (D1cc), and 2cc(D2cc) (in Gy) for the rectumand the bladder in periods 1through 4 (e.g., fractions 2through 5) |
|---|---|---|---|
| Exploratory Objectives:1) To estimate the difference inparticipant-reported discomfortbetween BVHPS and standardvaginal packing2) To estimate the difference inphysician/physicist evaluationof imaging clarity of thepacking and completeness ofpacking between BVHPS andstandard vaginal packing.3) To estimate the difference inphysician-scored useexperience between BVHPSand standard vaginal packing | Exploratory Endpoints:1) Participant-reported discomfortfrom packing scored on a 4-point scale for periods 2through 4 (e.g. fractions 2through 5).2) Physician/physicist evaluationof imaging clarity and packingand completeness of packingscored on a 4-point scale forperiods 1 through 4 (e.g.,fractions 2 through 5).3) Physician-scored useexperience scored on a 4-pointscale for periods 1 through 4(e.g., fractions 2 through 5). |
Study Design
Randomization was performed to determine the sequence of alternating BVHPS versus gauze packing for comparison, and to reduce the impact of timing on patient experience of the packing and on the impact of tumor response (Figure 2).
Image /page/7/Figure/3 description: The image shows a diagram of a study design with two arms, A and B. The study begins with randomization to either Arm A or Arm B, followed by registration and five periods of brachytherapy (Fx 1-5). Arm A involves standard packing in periods 1, 2, and 4, and BrachyGel packing in periods 3 and 5. Arm B involves standard packing in periods 1, 3, and 5, and BrachyGel packing in periods 2 and 4.
Figure 2. Study Schema
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A CT scan was obtained with each fraction of brachytherapy after placement of the applicators and vaginal packing for brachytherapy planning. There were no additional imaging studies or repacking prior to treatment.
All subjects enrolled in both arms of the study remained in the study for a maximum of thirty (30) days, or until they were discontinued or withdrew from the study.
Sample Size
The actual sample size did not achieve the pre-specified sample size calculated through power analysis. The study accrued a total of twenty (20) evaluable patients out of a planned enrollment of forty (40) evaluable patients at a single site.
Patients
Eligible participants were adult women (≥ 18 years old) with FIGO Stages IB2-IVA cervical cancer receiving definitive chemo-radiation with HDR brachytherapy boost with intra-cavitary +/- interstitial applicators. Twenty-one (21) patients were enrolled, and twenty (20) subjects were evaluated as the per protocol population, with one patient not treated due to disease progression. Exclusion criteria included: prior abdominal radiation therapy, prior a hysterectomy and/or contraindications to brachytherapy.
| Table 3. Patient Demographics | |
|---|---|
| BVHPS (n = 20) | |
| Age, mean years (range) | 52 (34 - 71) |
| Gender, # (%) | |
| Female | 20 (100.0%) |
| Male | 0 |
| ECOG Status, # (%) | |
| 0 | 14 (70.0%) |
| 1 | 6 (30.0%) |
| FIGO Stage, # (%) | |
| IB1 | 1 (5.0%) |
| IB2 | 1 (5.0%) |
| IIA | 1 (5.0%) |
| IIB | 7 (35.0%) |
| IIIA | 0 |
| IIIB | 0 |
| IIIC | 7 (35.0%) |
| IVA | 3 (15.0%) |
| IVB | 0 |
| Histology, # (%) | |
| Squamous cell carcinoma | 14 (70.0%) |
| Adenocarcinoma | 5 (25.6%) |
| Sarcomatoid carcinoma, HPV+ | 1 (5.0%) |
| Race, # (%) | |
| Asian | 1 (5.0%) |
| White | 17 (85.0%) |
| Other (Hispanic / Latino) | 2 (10.0%) |
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| Ethnicity, # (%) | |
|---|---|
| Hispanic or Latino | 2 (10.0%) |
| Non-Hispanic | 18 (90.0%) |
| # Fractions, # (%) | |
| 4 | 2 (10.0%) |
| 5 | 18 (90.0%) |
| Treatment Duration (mean days) | |
| Arm A | $10.8 \pm 2.2$ |
| Arm B | $15.0 \pm 7.8$ |
Results
A total of 5 physicians at the University of Virginia performed BVHPS insertion and removal during the clinical trial. One or two therapy bags were utilized for each case, depending on the patient anatomy and brachytherapy applicator placement daily. The longest duration of use for a single fraction was five hours. Dose summation reports were provided, showing that the patients received the intended doses to the target volumes (high risk clinical target volume (HR-CTV)).
Primary Endpoint Analysis
The dosimetry results for the D2cc bladder and rectum and the HR-CTV for Fractions 2 and 3 are shown in the tables below. There was no evidence to show that the D2cc for bladder or rectum is different between the subject device and standard gauze packing, with high variability of dosimetric results, as may be expected given the clinical context and the sample size.
| Table 4. Bladder Dosimetry for Fractions 2 and 3* | |||||
|---|---|---|---|---|---|
| Gauze Packing | BVHPS | ||||
| Subjectnumber | Prescribed doseper fraction(Gy)** | D2cc | Prescribed doseper fraction(Gy)** | D2cc | D2ccDifference(GauzePacking -BVHPS) |
| 01-002 | 6.63 | 4.19 | 5.03 | 3.36 | 0.83 |
| 01-003 | 6.49 | 2.77 | 6.96 | 4.14 | -1.37 |
| 01-004 | 6.23 | 2.21 | 5.53 | 3.2 | -0.99 |
| 01-005 | 5.9 | 3.73 | 5.9 | 3.79 | -0.06 |
| 01-006 | 5.13 | 3.75 | 5.74 | 3.42 | 0.33 |
| 01-007*** | |||||
| 01-008 | 6.04 | 2.25 | 8.41 | 2.48 | -0.23 |
| 01-009 | 5.04 | 3.39 | 6.16 | 2.41 | 0.98 |
| 01-010 | 6.54 | 3.8 | 6.37 | 3.23 | 0.57 |
| 01-011 | 5.86 | 4.71 | 6.99 | 4.32 | 0.39 |
| 01-012 | 5.49 | 4.58 | 6.89 | 2.17 | 2.41 |
| 01-013 | 8.66 | 3.49 | 5.1 | 4.28 | -0.79 |
| 01-014 | 7.56 | 2.94 | 5.92 | 3.28 | -0.34 |
| 01-015 | 6.01 | 4.46 | 4.51 | 3.54 | 0.92 |
| 01-016 | 7.03 | 3.19 | 6.58 | 3.03 | 0.16 |
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| 01-017 | 5.85 | 3.22 | 6.54 | 3.99 | -0.77 |
|---|---|---|---|---|---|
| 01-018 | 9.24 | 3.66 | 6.4 | 3.22 | 0.44 |
| 01-019 | 6.76 | 4.12 | 6.32 | 4.81 | -0.69 |
| 01-020 | 5.81 | 3.93 | 6.31 | 3.46 | 0.47 |
| 01-021 | 7.57 | 2.81 | 7.97 | 3.78 | -0.97 |
| Mean | 6.52 | 3.54 | 6.30 | 3.47 | 0.07 |
| Standard Deviation | 1.11 | 0.73 | 0.95 | 0.68 | 0.91 |
*D2cc: Dose to the hottest 2 cc of the organ at risk, bladder, Gy: Gray
** HRCTV D90
*** Patient 01-007 was not considered in the Per Protocol population for the primary endpoint because a not per protocol standard packing was utilized for fraction #2 in place of the per protocol BVHPS.
| Table 5. Rectal dosimetry for Fractions 2 and 3* | |||||
|---|---|---|---|---|---|
| Gauze Packing | BVHPS | ||||
| Subjectnumber | Prescribed doseper fraction(Gy)** | D2cc (Gy) | Prescribed doseper fraction(Gy)** | D2cc (Gy) | D2ccDifference(GauzePacking -BVHPS) |
| 01-002 | 6.63 | 2.87 | 5.03 | 3.24 | -0.37 |
| 01-003 | 6.49 | 2.94 | 6.96 | 3.15 | -0.21 |
| 01-004 | 6.23 | 3.79 | 5.53 | 4.24 | -0.45 |
| 01-005 | 5.9 | 3.45 | 5.9 | 3.42 | 0.03 |
| 01-006 | 5.13 | 3.19 | 5.74 | 3.54 | -0.35 |
| 01-007*** | |||||
| 01-008 | 6.04 | 2.8 | 8.41 | 3.56 | -0.76 |
| 01-009 | 5.04 | 2.35 | 6.16 | 3.16 | -0.81 |
| 01-010 | 6.54 | 3.08 | 6.37 | 2.39 | 0.69 |
| 01-011 | 5.86 | 3.38 | 6.99 | 2.76 | 0.62 |
| 01-012 | 5.49 | 3.41 | 6.89 | 4.06 | -0.65 |
| 01-013 | 8.66 | 4.36 | 5.1 | 3.47 | 0.89 |
| 01-014 | 7.56 | 2.52 | 5.92 | 3.01 | -0.49 |
| 01-015 | 6.01 | 2.73 | 4.51 | 2.57 | 0.16 |
| 01-016 | 7.03 | 3.06 | 6.58 | 3.06 | 0.00 |
| 01-017 | 5.85 | 1.82 | 6.54 | 2.19 | -0.37 |
| 01-018 | 9.24 | 3.28 | 6.4 | 3.44 | -0.16 |
| 01-019 | 6.76 | 2.34 | 6.32 | 3.43 | -1.09 |
| 01-020 | 5.81 | 3.29 | 6.31 | 2.8 | 0.49 |
| 01-021 | 7.57 | 3.39 | 7.97 | 3.85 | -0.46 |
| Mean | 6.52 | 3.06 | 6.30 | 3.23 | -0.17 |
| StandardDeviation | 1.11 | 0.57 | 0.95 | 0.55 | 0.54 |
*D2cc: Dose to the hottest 2 cc of the organ at risk, rectum, Gy: Gray
** HRCTV D90
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*** Patient 01-007 was not considered in the Per Protocol population for the primary endpoint because a not per protocol standard packing was utilized for fraction #2 in place of the per protocol BVHPS.
Additionally, the proportion of prescribed dose, defined as dose to structure/prescribed dose to HR-CTV D90, was calculated for each patient, and the results showed that there were no clinically meaningful differences between the packing mechanisms. See Tables 6 and 7 below.
| Table 6. Bladder D2cc comparison for Fractions 2 and 3 (Percentage of HR-CTV D90) | ||||
|---|---|---|---|---|
| Percentage of HR-CTV D90(Gauze Packing) (%) | Percentage of HR-CTV D90(BVHPS) (%) | Difference inPercentages (Gauze -BVHPS) (%) | ||
| Mean | 55.96 | 56.53 | -0.57 | |
| Standard Deviation | 16.0 | 14.5 | 20.8 |
| Table 7. Rectum D2cc comparison for Fractions 2 and 3 (Percentage of HR-CTV D90) | |||
|---|---|---|---|
| Percentage of HR-CTV D90(Gauze Packing) (%) | Percentage of HR-CTV D90(BVHPS) (%) | Difference inPercentages (Gauze -BVHPS) (%) | |
| Mean | 47.50 | 51.74 | -4.90 |
| Standard Deviation | 9.9 | 11.0 | 11.9 |
Secondary Endpoint Analysis - Adverse Events
| Table 8: All Adverse Events | ||||||
|---|---|---|---|---|---|---|
| Subject | Arm | CTC AE v5Description | AE Times | ToxicityGrade | Relation toBrachytherapy | Relation toBVHPS |
| 01-001 | NONE | |||||
| 01-002 | B | Vaginalinflammation | Between fraction 2 and 3 | 1 | Unrelated | Definite |
| 01-002 | B | VaginalHemorrhage | Between fraction 5 and 30day follow-up | 1 | Unrelated | Unrelated |
| 01-003 | B | Dysuria | Between fraction 2 and 3 | 1 | Unrelated | Unrelated |
| 01-003 | B | Dizziness | Between fraction 3 and 4 | 2 | Unlikely | Unrelated |
| 01-003 | B | Fatigue | Between fraction 3 and 4 | 2 | Probable | Unrelated |
| 01-003 | B | Nausea | Between fraction 3 and 4 | 2 | Probable | Unrelated |
| 01-003 | B | Vomiting | Between fraction 3 and 4 | 2 | Probable | Unrelated |
| 01-003 | B | Vaginal pain | Fraction 4 | 2 | Definite | Definite |
| 01-004 | B | Diarrhea | Fraction 1 | 1 | Probable | Unrelated |
| 01-004 | B | Vaginalhemorrhage | Fraction 2 | 1 | Definite | Definite |
| 01-004 | B | Bloating | Fraction 2 | 1 | Unrelated | Unrelated |
| 01-004 | B | Vaginal dryness | Fraction 2 | 1 | Probable | Unrelated |
| 01-004 | B | Fatigue | Between fraction 5 andfollow up | 1 | Possible | Unrelated |
| 01-004 | B | Dysuria | Between fraction 5 and 30day follow up | 1 | Unrelated | Unrelated |
| 01-004 | B | Pelvic pain | Between fraction 5 andfollow up | 1 | Unrelated | Unrelated |
| 01-004 | B | Pelvic pain | Between fraction 5 andfollow up | 3 | Unrelated | Unrelated |
| 01-005 | A | Dysuria | Fraction 5 | 2 | Unrelated | Unrelated |
| 01-005 | A | Vaginal pain | Fraction 5 | 2 | Definite | Definite |
| 01-005 | A | Fatigue | Between fraction 5 and follow up | 1 | Definite | Unrelated |
| 01-006 | A | Pelvic pain | Between fraction 5 and follow up | 1 | Unrelated | Unrelated |
| 01-006 | A | Fatigue | Between fraction 5 and follow up | 1 | Possible | Unrelated |
| 01-006 | A | Urinary urgency | Between fraction 5 and follow up | 1 | Possible | Unrelated |
| 01-006 | A | Diarrhea | Between fraction 5 and follow up | 1 | Possible | Unrelated |
| 01-007 | B | Pelvic pain | Between fraction 1 and 2 | 2 | Possible | Unlikely |
| 01-008 | A | Constipation | Between fraction 5 and 30 day follow up | 1 | Unrelated | Unrelated |
| 01-009 | NONE | |||||
| 01-010 | B | Pelvic pain | Fraction 3 | 2 | Probable | Unrelated |
| 01-010 | B | Vaginal pain | Fraction 4 | 1 | Probable | Unrelated |
| 01-010 | B | Vaginal hemorrhage | Fraction 5 | 1 | Unlikely | Unrelated |
| 01-010 | B | Vaginal discharge | Between fraction 5 and 30 day follow up | 1 | Possible | Unrelated |
| 01-010 | B | Vaginal pain | Between fraction 5 and 30 day follow up | 1 | Possible | Unrelated |
| 01-011 | A | Infections and infestations | Baseline | 3 | Unrelated | Unrelated |
| 01-011 | A | Vaginal pain | Fraction 2 | 1 | Definite | Unrelated |
| 01-011 | A | Dermatitis radiation | Between fraction 2 and 3 | 2 | Unrelated | Unrelated |
| 01-011 | A | Facial pain | Between fraction 5 and follow-up | 1 | Unrelated | Unrelated |
| 01-011 | A | Urinary tract infection | Between fraction 5 and follow-up | 2 | Possible | Unlikely |
| 01-013 | B | Dyspareunia | Between fraction 4 and 30 day follow up | 1 | Possible | Unlikely |
| 01-014 | NONE | |||||
| 01-015 | B | Vaginal inflammation | Fraction 2 | 2 | Probable | Unrelated |
| 01-015 | B | Vaginal pain | Fraction 2 | 2 | Probable | Unrelated |
| 01-015 | B | Vaginal hemorrhage | Fraction 3 | 1 | Unlikely | Possible |
| 01-015 | B | Vaginal inflammation | Fraction 4 | 1 | Probable | Unrelated |
| 01-015 | B | Vaginal infection | Fraction 4 or between fraction 3 and 4 | 1 | Unrelated | Unrelated |
| 01-016 | NONE | |||||
| 01-017 | NONE | |||||
| 01-018 | A | Vaginal pain | Fraction 2 | 2 | Definite | Unrelated |
| 01-019 | B | Pelvic pain | Fraction 3 | 2 | Unlikely | Unrelated |
| 01-020 | NONE | |||||
| 01-021 | A | Anemia | Fraction 4 | 3 | Unlikely | Unrelated |
| 01-021 | A | Dermatitis radiation | Between fraction 4 and 30 day follow up | 2 | Probable | Unrelated |
| 01-021 | A | Anorexia | Between fraction 4 and follow up | 1 | Possible | Unrelated |
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All BVHPS subject adverse events were reviewed for relationship to the investigational device. There were three events which did or may have occurred in relationship to the investigational device and are summarized in the table below.
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| Table 9: Relationship to BVHPS | ||
|---|---|---|
| Event Type | Relationship | Description |
| Grade 2 Vaginal Pain | Definitely | Recovered/resolved without sequelae |
| Grade 1 VaginalHemorrhage | Definitely | Spotting; Recovered/resolved without sequelae |
| Grade 2 Vaginal Pain | Definitely | Recovered/resolved without sequelae |
Secondary Endpoint Analysis - Dose to D0.1cc, D1cc, and D2cc in periods 1 through 4 (e.g., fractions 2 through 5)
The results suggest no clinically meaningful differences in bladder and rectal dosimetry values between the two packing mechanisms.
Exploratory Endpoints - Surveys
The exploratory objectives of the study involved clinician and patient surveys. These objectives included (1) an estimation in the participant-reported discomfort between BVHPS and standard vaginal packing; (2) an estimation of the difference in physicist evaluation of imaging properties and completeness of packing between BVHPS and standard packing (as evaluated by physical exam and CT imaging); and (3) an estimation of the difference in physician-scored use experience between BVHPS and standard vaginal packing. See a summary of the results of the assessment surveys in the table below.
| Table 10: Clinician and Patient Surveys | Standard Packingn (%) | BVHPSn (%) |
|---|---|---|
| Patient | ||
| Discomfort during the entire brachytherapy treatment (n = 57)* | ||
| • none | 1 (3.7%) | 2 (6.7%) |
| • mild | 11 (40.7%) | 14 (46.7%) |
| • moderate | 14 (51.9%) | 10 (33.3%) |
| • severe | 1 (3.7%) | 4 (3.3%) |
| Discomfort during vaginal packing placement and removal (n = 57)* | ||
| • none | 2 (7.4%) | 7 (23.3%) |
| • mild | 12 (44.4%) | 11 (36.7%) |
| • moderate | 8 (29.6%) | 10 (33.3%) |
| • severe | 5 (18.5%) | 2 (6.7%) |
| Physician | ||
| Completeness of the packing (n = 77) | ||
| • excellent | 3 (7.7%) | 5 (13.1%) |
| • good | 19 (48.7%) | 25 (65.8%) |
| • fair | 14 (35.9%) | 7 (18.4%) |
| • poor | 3 (7.7%) | 1 (2.6%) |
| Imaging clarity of the packing (n = 77) | ||
| • very clear | 9 (23.1%) | 0 |
| • clear | 17 (43.6%) | 23 (60.5%) |
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| • poor | 13 (33.3%) | 15 (39.5%) |
|---|---|---|
| • no distinction | 0 | 0 |
| Ease of packing placement and removal (n = 62) ** | ||
| • extremely easy | 0 | 7 (21.1%) |
| • somewhat easy | 21 (72.4%) | 22 (66.7%) |
| • somewhat difficult | 8 (27.6%) | 2 (6.1%) |
| • extremely difficult | 0 | 2 (6.1%) |
| Physicist | ||
| Completeness of the packing (n = 77) | ||
| • excellent | 10 (25.6%) | 17 (44.7%) |
| • good | 21 (53.9%) | 16 (42.1%) |
| • fair | 6 (15.4%) | 5 (13.2%) |
| • poor | 2 (5.1%) | 0 |
| Imaging clarity of the packing (n = 77) | ||
| • very clear | 15 (38.5%) | 12 (31.6%) |
| • clear | 20 (51.3%) | 21 (55.3%) |
| • poor | 4 (10.3%) | 3 (7.9%) |
| • no distinction | 0 | 2 (5.3%) |
| * Surveys were not completed by patients who underwent anesthesia as the patient was not awake and unable to assess |
no distinction p
** One physician did not have surveys performed due to a conflict of interest and involvement with the device manufacturer.
The participant surveys were administered to patients within one hour of the brachytherapy procedure for any procedure that was not administered under anesthesia (i.e., the participant was awake and able to assess the experience).
The clinician surveys were completed by the physician and physicist performing the brachytherapy procedures. Clinician assessment of packing completeness was based on physical examination and CT imaging. The results of the physician surveys showed that the BVHPS device received a larger proportion of favorable ease-of-use scores than gauze. Investigator observations from the clinical trial included that the BVHPS device remained solid, and in appropriate position, throughout the treatment planning and delivery process.
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.
Conclusions
The results of the clinical study support that there are no clinically meaningful differences in the D2cc in the rectum and bladder for BVHPS vs. standard gauze packing. As the trial did not meet the powered accrual number, non-inferiority could not be statistically determined. However patient accrual was sufficient to judge comparability of D2cc between the two methods. Additionally, the use of BVHPS on patients receiving intracavitary brachytherapy for cervical cancer was not associated with an increase in serious adverse events compared to the standard packing control group.
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The patient survey results suggested less patient discomfort due to BVHPS placement and removal when compared to gauze. The clinician and physicist surveys also support favorable ease of use and completeness of packing. Variable results were observed for clarity on imaging, with fewer physicians describing BVHPS as "very clear" on CT imaging compared to gauze.
LABELING
The labeling consists of Instructions for Use and an exterior device label.
The Instructions for Use include a device description, Indications for Use, Contraindications, Warnings, Instructions on insertion, installation, and removal, the functional use life of the device, expiration date, a summary of the clinical results including adverse events, and an example CT image of the device in a patient.
The device label includes the expiration date.
The labeling meets the requirements of 21 CFR 801.109 for prescription devices.
RISKS TO HEALTH
The table below identifies the risks to health that may be associated with use of a vaginal hydrogel packing system and the measures necessary to mitigate the risks.
| Risks to Health | Mitigation Measures |
|---|---|
| Unintended irradiation of healthy tissueand/or underdosing of the target | Clinical performance dataPerformance testingLabeling |
| Tissue damage from device instability,failure, or removal | Clinical performance dataNon-clinical performance testingLabeling |
| Infection | Sterilization validationNon-clinical performance testingLabelingShelf life testing |
| Adverse tissue reaction | Biocompatibility evaluation |
| Prolonged or delayed procedure due todelays caused by device deployment,instability, or failure | Clinical performance dataLabeling |
| Patient discomfort | Clinical performance dataLabeling |
SPECIAL CONTROLS
In combination with the general controls of the FD&C Act, the vaginal hydrogel packing system is subject to the following special controls:
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- (1) Clinical performance data must demonstrate the device performs as intended under anticipated conditions of use and evaluate the following:
- Radiation dose to adjacent organs at risk; (i)
- (ii) Device stability;
- (iii) Ability to deploy, expand, and remove the device; and
- Patient comfort. (iv)
- (2) Non-clinical performance testing must demonstrate that the device performs as intended under anticipated conditions of use. Testing must include:
- Testing to evaluate the effect of therapeutic radiation levels on device integrity; (i)
- Bioburden testing to demonstrate the device does not pose an infection risk, if the (ii) device is not provided sterile; and
- Structural integrity testing of the container, including tensile strength, container (iii) leakage, and burst strength.
- Performance testing must demonstrate space creation and maintenance for the duration (3) of a radiation treatment fraction.
- (4) The patient-contacting components of the device must be demonstrated to be biocompatible.
- (૨) Performance data must demonstrate the sterility of patient-contacting components of the device that are provided sterile.
- Performance data must support the shelf life of the device by demonstrating package (6) integrity and device functionality over the labeled shelf life
- Labeling must include: (7)
- Warnings that: (i)
- A 3-dimensional (3D) imaging method is needed to ensure the device is (A) placed correctly; and
- Failure to perform the standard imaging position verification protocol may (B) cause the device to not perform as intended.
- Instructions on how to proceed if the device fails to perform as intended; (ii)
- A summary of clinical data relevant to the device, including device-related (iii) complications; and
- An expiration date or shelf life. (iv)
- Warnings that: (i)
BENEFIT-RISK DETERMINATION
The probable risks are based on nonclinical laboratory data and data collected from the clinical study described above. The probable risks include: 1) Unintended irradiation of healthy tissue and/or underdosing of the target, 2) Tissue damage from applicator instability, failure, or removal, 3) Infection, 4) Adverse tissue reaction, 5) Prolonged or delayed procedure due to delays caused by device deployment, instability, or failure, 6) Patient discomfort.
The probable benefits of the device are also based on nonclinical laboratory data and data collected from the clinical study described above. The probable benefit of the device compared to the standard is that the gel is easier to remove and more comfortable for the patient. The current standard of care is gauze packing which may be more cumbersome and time-consuming. and it may cause more discomfort to the patient during removal. The sponsor demonstrated that there was no clinically meaningful difference in dose to organs at risk (OARs) and the tumor
{17}------------------------------------------------
when comparing standard gauze packing to the subject device in a clinical study. The sponsor also provided questionnaires that indicated that the physicians favored the device over standard gauze based on ease of placement and removal and packing assessment, and patient surveys indicated that they had less discomfort with the device compared to standard gauze.
Patient Perspectives
This submission included patient surveys which evaluated discomfort during the brachytherapy treatment and during the vaginal packing placement and removal. See results of the surveys above in the section "Summary of Clinical Information" > "Results" > "Exploratory Endpoints - Surveys"
Benefit/Risk Conclusion
In conclusion, given the available information above, for the following indication statement:
The BrachyGel Vaginal Hydrogel Packing System is a single-use, non-sterile, disposable, non-powered positioning device that delivers self-expanding hydrogel that forms and expands within the vaginal cavity. The purpose of this device is to displace the vaginal wall and adjacent pelvic tissues during radiation therapy planning and delivery, to reduce dose to adjacent tissues by attenuation of radiation dose, and to stabilize radiation treatment equipment during radiation therapy planning and delivery. The placement of the hydrogel device requires a physician directed healthcare professional. and is performed as a separate procedure outside of brachytherapy applicator insertion, computed tomography and/or magnetic resonance imaging exam, radiation treatment planning and radiation treatment delivery. This device is not intended to be inserted into the uterine cavity or rectum. This device is intended to be in place temporarily and removed after less than 24 hours.
Though the probable risks are unintended radiation to healthy tissue and underdosing of the target, as well as adverse effects to the healthy tissue and patient, the probable benefit of the device is that it is easier to remove and more comfortable for the patient than the standard of care. The probable benefits outweigh the probable risks for the BrachyGel Vaginal Hydrogel Packing System. 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 BrachyGel Vaginal Hydrogel Packing System is granted and the device is classified as follows:
Product Code: QXR Device Type: Vaginal hydrogel packing system Regulation Number: 21 CFR 892.5735 Class: II
N/A