(269 days)
The Vibrant System is an orally administered Capsule that is indicated for the treatment of adults with chronic idiopathic constipation who have not experienced relief of their bowel symptoms by using laxative therapies at the recommended dosage for at least one month.
The Vibrant System is comprised of two components; a Pod and a single use Capsule. The Pod activates the Capsule using radio frequency (RF) communication. After activation, the Capsules are taken orally. After a pre-programmed activation delay, the Capsules begin to vibrate. The marketed device will have an activation delay of 14 hours. (The 14 hours activation delay corresponds to Active Mode 1 of the pivotal study described below: the pivotal study also included an Active Mode 2 with a 9 hour activation delay.) As they pass through the gastrointestinal tract, the Capsules vibrate for four pre-programmed periods of 100 min, 120 min, 100 min. 180 min. It takes about three days for the Capsules to pass through the gastrointestinal tract, at which point thev are excreted in a bowel movement.
The Capsule is comprised of a motor that vibrates (2.5 Vdc. 70 ma), electronic card, batteries (2x 1.5V 60 mAh, alkaline/0% Hg coin battery) and connector. The capsule is a two-piece shell made from Polycarbonate Makrolon 2458. The Capsule dimensions are as follows: length: 24.5 ± 0.1 mm; diameter: 11.20 ± 0.05 mm; weight 4.0 ± 0.1 g. The Capsules have a vibration force between 200 and 550 gf, with vibration cycles of 3 seconds on and16 seconds off (190 cycles per hour).
Here's a breakdown of the acceptance criteria and the study proving the device meets them, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The provided text details acceptance criteria for bench testing and clinical effectiveness.
Bench Testing Acceptance Criteria & Results (from Table 1)
| Test | Acceptance Criteria | Reported Device Performance |
|---|---|---|
| Mechanical Integrity | No cracks, ruptures, loose particles, or debris are observable following (b)(4) application of (b)(4) | Pass |
| Seal test | No major leak, and the pressure of the test capsule must be less than (b)(4) the control capsule pressure. | Pass |
| pH Resistance | Capsules must not show defects in the seal, no ruptures, no shell cracks, or any other damage to the capsule. The Capsules must also pass the sealing | Pass |
| Mode of Operation | Capsules must meet the predefined specifications for start time, duration, vibrational force, vibrational sequence. | Pass |
| Dimensional | Capsule length must be (b)(4) Capsule diameter must be (b)(4) | Pass |
| Visual Inspection | External surface of Capsule is free of surface defects and extraneous matter. | Pass |
Clinical Effectiveness Acceptance Criteria & Results (from "Effectiveness results" section for mITT analysis set)
| Endpoint | Acceptance Criteria (Study Success Definition) | Reported Device Performance |
|---|---|---|
| Primary Effectiveness Endpoint: | Either CSBM1 or CSBM2 success rate being statistically significantly higher in the active arm (Active Mode 1) than in the control arm, as evaluated in the mITT population. | Met. Both CSBM1 and CSBM2 success rates were statistically significantly higher in the active arm compared to the control. |
| CSBM1 Success Rate | Increase from the run-in period of at least one weekly CSBM during at least 6 of the 8 weeks of treatment, with a statistically significantly higher rate in the active arm vs. control. | 40.51% in Treatment (Active Mode 1) vs. 22.92% in Control. Difference of 17.6% (chi-square p-value = 0.0011). Statistically significant. |
| CSBM2 Success Rate | Increase from the run-in period of at least two weekly CSBM during at least 6 of the 8 weeks of treatment, with a statistically significantly higher rate in the active arm vs. control. | 23.42% in Treatment (Active Mode 1) vs. 11.81% in Control. Difference of 10.0% (chi-square p-value = 0.0085). Statistically significant. |
| Primary Safety Endpoint: All Adverse Events (AEs) | Not explicitly stated as a numerical acceptance criterion, but the study was designed to evaluate all AEs related and unrelated to the treatment. The implication is that the safety profile should be acceptable for the intended use, and risks should be mitigable. | Acceptable. 114 AEs reported (74 in treatment, 40 in control). No SAEs in treatment arms. 49 AEs considered related (41 in treatment, 8 in control). Most common device-related AE was "sensation of vibration" (9.5%). |
| Secondary Endpoints: Straining | Observed reduction in straining in the active arm compared to the control arm. | Observed reduction. Adj. Mean change from baseline: Treatment -1.78, Control -1.32. Diff (Treatment-Control): -0.46 ([-0.95; 0.03]). |
| Stool Consistency (Bristol Stool Scale) | Observed improvement in stool consistency in the active arm compared to the control arm. | Observed improvement. Adj. Mean change from baseline: Treatment 1.03, Control 0.58. Diff (Treatment-Control): 0.45 ([0.19; 0.71]). |
| Bloating Sensation | No difference was observed in the bloating sensation endpoint. (This appears to be an observed finding rather than a strict acceptance criterion for improvement). | No difference observed. Adj. Mean change from baseline: Treatment -0.42, Control -0.37. Diff (Treatment-Control): -0.06 ([-0.42; 0.30]). |
Study Proving Device Meets Acceptance Criteria
The primary study proving the device meets the acceptance criteria is the V270 pivotal study.
The V270 study was described as:
- Design: Prospective, randomized, multi-center, double-blinded, placebo-controlled pivotal study.
- Arms: Initially two active treatment arms (Active Mode 1 and Active Mode 2) and a control arm. Active Mode 2 was dropped after interim analysis, continuing with Active Mode 1 and control.
- Treatment Duration: 8 weeks.
- Population: Adults with chronic idiopathic constipation (CIC) refractory to existing OTC or Rx treatments or intolerant of side effects.
Additional Information:
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size for Test Set (Clinical Study - V270):
- Consented and Screened: 904 subjects
- Randomized (ITT analysis set): 349 subjects (Active Mode 1: 163, Active Mode 2: 37, Control: 149)
- Modified Intent-to-Treat (mITT) analysis set: 336 subjects (Active Mode 1: 158, Active Mode 2: 34, Control: 144) - This was the primary effectiveness analysis population.
- Per Protocol (PP) analysis set: 333 subjects (Active Mode 1: 155, Active Mode 2: 34, Control: 144)
- Primary Safety Analysis Set (ITT): 349 subjects (Active Mode 1 & 2 combined: 200, Control: 149)
- Data Provenance: The document does not explicitly state the country of origin for the clinical study data but mentions the sponsor information is Vibrant Ltd. Hakochav P.O. Box 516 Yokneam, Israel. Given it's a pivotal FDA study, it often involves sites in the US and potentially other regions, but this is not specified. The study was prospective.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Their Qualifications
- For this type of device (orally ingested capsule for constipation), the "ground truth" for effectiveness endpoints (CSBMs, straining, stool consistency, bloating) is patient-reported outcomes (PROs) based on diary entries. These outcomes are not typically established by "experts" in the sense of image readers or diagnosticians.
- For safety, adverse events were reported by subjects and assessed by study investigators, who are implicitly qualified medical professionals overseeing the clinical trial. The document doesn't specify the number or specific qualifications (e.g., years of experience) of these investigators beyond them being the "study investigators."
4. Adjudication Method for the Test Set
- The text does not mention an "adjudication method" in the context of expert review for establishing ground truth, as the primary effectiveness endpoints are patient-reported.
- For adverse events, "study investigators" classified AEs as "possibly, probably, or definitely related to the study treatment or procedure" (Table 8), implying an internal review process, but no specific multi-reviewer adjudication method (like 2+1 or 3+1) is described.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size of How Much Human Readers Improve with AI vs. Without AI Assistance
- No, an MRMC comparative effectiveness study was not done. This device is a therapeutic capsule, not an AI-assisted diagnostic tool that would involve human readers interpreting cases. Therefore, the concept of improving human readers with AI assistance does not apply.
6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done
- This device is a physical, orally ingested capsule with pre-programmed vibration patterns. It does not involve an "algorithm" in the sense of AI performing a diagnostic task. The "algorithm" here refers to the embedded software controlling the capsule's operation (vibration start time, duration, sequence, rest time). The performance of this software in controlling the physical device was assessed via bench testing ("Mode of Operation" test).
7. The Type of Ground Truth Used
- The primary ground truth for effectiveness was patient-reported outcomes (PROs) from daily diaries (e.g., number of CSBMs, straining levels, Bristol Stool Scale scores, bloating).
- The ground truth for safety was adverse events reported by subjects and assessed by investigators.
8. The Sample Size for the Training Set
- This is not an AI/machine learning device that typically has a separate "training set" for model development. The "training" for this device would be its design, engineering, and iterative testing, not data-driven model training.
- The various non-clinical (bench) and animal studies served as early development and validation steps prior to the pivotal human clinical trials. Five smaller clinical trials involving a total of 499 subjects were conducted prior to V270, but these did not fully support effectiveness and are mentioned as providing cumulative safety data, not as a "training set" for an algorithm.
9. How the Ground Truth for the Training Set Was Established
- As this is not an AI/machine learning device with a typical "training set," this question is not directly applicable. The "ground truth" for the development and bench testing of the capsule's physical and functional properties would be established through engineering specifications, physical measurements, and adherence to biological/physiological parameters (e.g., pH conditions, vibration specifications).
- For the earlier clinical trials (499 subjects), the ground truth for safety and preliminary effectiveness would have been established similarly to the pivotal study – patient-reported outcomes and investigator assessment of adverse events.
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DE NOVO CLASSIFICATION REQUEST FOR VIBRANT SYSTEM
REGULATORY INFORMATION
FDA identifies this generic type of device as:
Orally ingested transient device for constipation. An orally ingested transient device for constipation is an electric swallowable capsule that naturally passes through the gastrointestinal tract for the treatment of constipation.
NEW REGULATION NUMBER: 21 CFR 876.5940
CLASSIFICATION: Class II
PRODUCT CODE: QTN
BACKGROUND
DEVICE NAME: Vibrant System
SUBMISSION NUMBER: DEN210052
DATE DE NOVO RECEIVED: December 1, 2021
SPONSOR INFORMATION: Vibrant Ltd. Hakochav P.O. Box 516 Yokneam, Israel, 2069206
INDICATIONS FOR USE
The Vibrant System is an orally administered Capsule that is indicated for the treatment of adults with chronic idiopathic constipation who have not experienced relief of their bowel symptoms by using laxative therapies at the recommended dosage for at least one month.
LIMITATIONS
The sale, distribution, and use of the Vibrant System is restricted to prescription use in accordance with 21 CFR 801.109.
The Vibrant capsules are contraindicated for use under the following conditions:
- History of complicated/obstructive diverticular disease .
- History of intestinal or colonic obstruction, or suspected intestinal obstruction .
- Clinical evidence of current and significant gastroparesis .
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- History of significant gastrointestinal disorder, including any form of inflammatory . bowel disease or gastrointestinal malignancy (celiac disease is accepted if the subject has been treated and is in remission), and/or anal fissures and fistulas
- History of Zenker's diverticulum, dysphagia, esophageal stricture, eosinophilic . esophagitis, or achalasia
- . Women who are pregnant or lactating
PLEASE REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.
DEVICE DESCRIPTION
The Vibrant System is comprised of two components; a Pod and a single use Capsule. The Pod activates the Capsule using radio frequency (RF) communication. After activation, the Capsules are taken orally. After a pre-programmed activation delay, the Capsules begin to vibrate. The marketed device will have an activation delay of 14 hours. (The 14 hours activation delay corresponds to Active Mode 1 of the pivotal study described below: the pivotal study also included an Active Mode 2 with a 9 hour activation delay.) As they pass through the gastrointestinal tract, the Capsules vibrate for four pre-programmed periods of 100 min, 120 min, 100 min. 180 min. It takes about three days for the Capsules to pass through the gastrointestinal tract, at which point thev are excreted in a bowel movement.
The Capsule is comprised of a motor that vibrates (2.5 Vdc. 70 ma), electronic card, batteries (2x 1.5V 60 mAh, alkaline/0% Hg coin battery) and connector. The capsule is a two-piece shell made from Polycarbonate Makrolon 2458. The Capsule dimensions are as follows: length: 24.5 ± 0.1 mm; diameter: 11.20 ± 0.05 mm; weight 4.0 ± 0.1 g. The Capsules have a vibration force between 200 and 550 gf, with vibration cycles of 3 seconds on and16 seconds off (190 cycles per hour).
Figure 1: Vibrant System: Capsule
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Figure 2: Vibrant System: Pod
Image /page/2/Picture/1 description: The image shows a white and blue device with a clear plastic lid that is open. The device has two circular indentations on the top, and a small, round, light-colored object is in the center of the indentations. There is a green light on the lower left corner of the device, and a black rectangular button is located near the bottom center.
SUMMARY OF NONCLINICAL/BENCH STUDIES
BIOBURDEN AND SHELF LIFE
The Vibrant System is not provided sterile. Vibrant Capsules are routinely monitored during manufacturing for bioburden levels to ensure the total bioburden is no greater than forming units per capsule. Packaging and shelf-life testing confirmed the Vibrant System packaging maintained integrity and device performance over the 1-year labeled shelf life. See Table 1 for list of bench testing conducted to support shelf-life.
SOFTWARE
The Vibrant System contains software to control the operation and vibration of the Capsule and for activation and time calibration of the Capsule by the Pod. Software verification and validation testing was performed and the results demonstrated the software functions as intended and all requirements specifications were met. The software/firmware was reviewed according to the "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices," dated May 11, 2005. The software has a moderate level of concern.
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ELECTROMAGNETIC COMPATIBILITY AND ELECTRICAL SAFETY
The Vibrant System conforms to the requirements for electrical safety and electromagnetic compatibility in ANSI AAMI ES60601-1:2005/@2012, A1:2012, C1:2009/(R)2012 and A2:2010/(R)2012; IEC 60601-1-11:2015; IEC 60601-1-2:2014.
BIOCOMPATIBILITY
The Vibrant capsules are classified as mucosal membrane contacting with a cumulative duration of exposure of >30 days. Capsule biocompatibility was evaluated in accordance with ISO 10993-1, Biological evaluation of medical devices and FDA Guidance: Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process". The following biocompatibility endpoints were evaluated with testing and chemical characterization/toxicological risk assessment:
- . cytotoxicity
- sensitization .
- irritation .
- acute systemic toxicity .
- materials mediated pyrogenicity .
- . subchronic toxicity
- genotoxicity .
- . chronic toxicity
The results of these evaluations support the biocompatibility of the Vibrant Capsules.
The Vibrant System Pod is non-patient contacting and biocompatibility assessment was not necessary.
PERFORMANCE TESTING - BENCH
The performance of the Vibrant Capsule was evaluated with the nonclinical bench testing summarized in Table 1.
| Test | Test Methods | Acceptance Criteria | Results |
|---|---|---|---|
| Mechanical Integrity | Capsules were placed under loads ranging from (b)(4) to (b)(4). The capsule was subjected to (b)(4) for (b)(4) | No cracks, ruptures, loose particles, or debris are observable following (b)(4) application of (b)(4) | Pass |
| Seal test | Capsule ultrasonic welds were evaluated for seal integrity using leak tester (b)(4) | No major leak, and the pressure of the test capsule must be less than (b)(4) the control capsule pressure. | Pass |
| pH Resistance | Capsules were incubated for (b)(4) in the worse-case pH conditions of pH (b)(4) | Capsules must not show defects in the seal, no ruptures, no shell cracks, or any other damage to the capsule. The Capsules must also pass the sealing | Pass |
Table 1: Summary of Performance Testing - Bench Studies
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| Test | Test Methods | Acceptance Criteria | Results |
|---|---|---|---|
| Mode of Operation | Following Capsule activation, thefollowing parameters were recorded:vibration start time, vibrationduration, vibration force, vibrationsequence and rest time. Theseparameters were recorded for each ofthe four vibration rounds. | Capsules must meet the predefinedspecifications for start time, duration,vibrational force, vibrationalsequence. | Pass |
| DimensionalVerification | A digital caliper was used to measurethe length and diameter of thecapsules. | Capsule length must be(b)(4)Capsule diameter must be(b)(4) | Pass |
| Visual Inspection | The Capsules were visually inspectedwith a magnifying glass to check theCapsule for correct assembly of theshell components, check for anydamage to the shell (e.g., scratches,kinks), and to check for the presenceof extraneous matter on the shell. | External surface of Capsule is free ofsurface defects and extraneous matter. | Pass |
PERFORMANCE TESTING - ANIMAL
An earlier version of the Vibrant Capsule was evaluated in proof-of-concept [ by ]studies. The testing evaluated preliminary safety and performance of the capsules. The studies did not identify any significant safety signals.
SUMMARY OF CLINICAL INFORMATION
A pivotal study (V270) was conducted to evaluate the safety and effectiveness of the Vibrant Capsules. The study was conducted in compliance with 21 CFR parts 50. 56, and 812. V270 was a prospective, randomized, multi-center, double-blinded, placebo-controlled pivotal study. The study included two active treatment arms that used different vibration patterns (i.e., Active Mode I and Active Mode 2) and a control arm. For the first part of the study, subjects were randomized equally to each arm in a 1:1:1 ratio, for a treatment period of 8 weeks. A "drop the loser" design was pre-specified, whereby the lower performing active treatment was dropped from the study following an interim analysis. After the lower performing active arm was dropped, future subjects were randomized to each of the remaining arms on a 1:1 ratio. The alpha value was adjusted to two-sided 0.025 to account for this design.
Vibrant Capsules were administered 5 times per week, and the treatment arm was compared to a control arm. The sham used in the control arm was a placebo consisting of a biodegradable softgel capsule filled with soybean oil, beeswax, and calcium carbonate. The study population was comprised of subjects with chronic idiopathic constipation (CIC) who were refractory to existing OTC or Rx treatments or could not tolerate with the side effects. Patient eligibility was assessed during the initial screening visit and was re-assessed and confirmed during the Baseline visit following a 2-3-week run-in period. Randomization occurred following the 2-3-week run-in
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period and verification that the patient satisfied all inclusion criteria and did not meet any exclusion criteria.
Endpoints
Primary Effectiveness endpoint
- Complete Spontaneous Bowel Movements (CSBM1) success rate, defined as an increase . from the run-in period of at least one weekly CSBM during at least 6 of the 8 weeks of treatment.
- · Complete Spontaneous Bowel Movements (CSBM2) success rate, defined as an increase from the run-in period of at least two weekly CSBM during at least 6 of the 8 weeks of treatment.
Study success was defined as either the CSBM1 or the CSBM2 success rate being statistically significantly higher in the active arm that was continued after interim analysis, than in the control arm, as evaluated in the modified Intent to Treat (mITT) population, which is described in the "Subject Accountability" section, below.
Primary Safety endpoint
All adverse events (AEs) related and unrelated to the study treatment, in the Intent to Treat (ITT) population, as described in the "Subject Accountability" section, below.
Secondary endpoints
- Change from baseline in average straining, using a scale from 0 (no straining) to 10 . (unbearable straining).
- Change from baseline in average stool consistency, using the Bristol Stool Scale. .
- . Change from baseline in average bloating, using a scale from 0 (no bloating) to 10 (unbearable bloating).
Selected additional secondary endpoints
- Treatment satisfaction score using the Treatment Satisfaction Questionnaire for Medication . (TSQM)
- . Change from baseline in quality of life using the Patient Assessment of Constipation Quality of Life Ouestionnaire (PAC-OOL) questionnaire
Subject accountability
A total of 904 subjects were consented and screened. 555 subjects were not randomized: 89% (493/555) were considered screen failures, 5% (28/555) withdrew consent prior to randomization, 2% (10/555) were lost to follow up before randomization, and the other 4% (24/555) for other reasons. A total of 349 consenting subjects were enrolled in the study and randomized. It was subsequently determined that one of the 349 randomized subjects did not meet the eligibility criteria, and 12/349 subjects had less than 2 weeks of diary entries with at least 5 days/week (requirement for randomization); these subjects were thus included in the Intention to Treat (ITT) analysis set but excluded from the modified ITT (mITT) analysis set. Three subjects in the mITT analysis set had major protocol deviations and were thus excluded from the Per Protocol (PP) analysis set. Subjects with less than 6 weeks of diary data were
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considered as failures for the CSBM1, and CSBM2 success rates. The final treatment allocation and analysis sets are shown in Table 2.
| Active Mode 1 | Active Mode 2 | Control | Total | |
|---|---|---|---|---|
| ITT analysis set | 163 | 37 | 149 | 349 |
| mITT analysis set | 158 | 34 | 144 | 336 |
| PP analysis set | 155 | 34 | 144 | 333 |
Table 2: Treatment Allocation
Patient demographics are shown in Table 3.
| Active Mode 1 | Active Mode 2 | Control | Total | p-value (Active Mode1 vs Control) | |||
|---|---|---|---|---|---|---|---|
| Age, | N | 163 | 37 | 149 | 349 | ||
| years | Mean(SD) | 47.1(13.33) | 45.0(12.25) | 45.9(13.47) | 46.4(13.26) | 0.4391(*) | |
| Median[Range] | 47.4[20.6;77.8] | 44.0[22.2:76.0] | 44.8[22.1;78.1] | 45.0[20.6:78.1] | |||
| Gender | Male | %(n/N) | 12.3%(20/163) | 24.3%(9/37) | 15.4%(23/149) | 14.9%(52/349) | |
| Female | %(n/N) | 87.7%(143/163) | 75.7%(28/37) | 84.6%(126/149) | 85.1%(297/349) | 0.4177(#) | |
| Race/Ethnicity | Caucasian | %(n/N) | 47.2%(77/163) | 59.5%(22/37) | 40.3%(60/149) | 45.6%(159/349) | 0.7624(#) |
| Hispanicor Latino | %(n/N) | 19.0%(31/163) | 8.1%(3/37) | 22.8%(34/149) | 19.5%(68/349) | ||
| Black orAfricanAmerican | %(n/N) | 25.2%(41/163) | 29.7%(11/37) | 26.2%(39/149) | 26.1%(91/349) | ||
| Asian/PacificIslander | %(n/N) | 6.1%(10/163) | 2.7%(1/37) | 8.1%(12/149) | 6.6%(23/349) | ||
| Other | %(n/N) | 2.5%(4/163) | - | 2.7%(4/149) | 2.3%(8/349) |
Table 3: Demographic Characteristics - ITT
(*) t-test
(#) x2 test
Effectiveness results
The pre-specified interim analysis was conducted on the results available from 116 enrolled subjects. At the interim analysis timepoint, the Active Mode 2 arm was dropped, and the study continued with only 2 arms: the most promising effectiveness treatment arm (Active Mode 1) and the control arm. The effectiveness results presented below are for the Active Mode 1 treatment arm and the control arm.
Table 4 presents the CSBM1 and CSBM2 success rates by study arm and analysis set. In the primary analysis population, the mITT set, the CSBM1 success rate was 40.51% in the treatment arm, compared to 22.92% in the control arm, a difference of 17.6% (chi-square p-value = 0.0011); and the CSBM2 success rate was 23.42% in the treatment arm, compared to 11.81% in the control arm, a difference of 10.0% (chi-square p-value = 0.0085). The primary effectiveness results met the study success criteria with both the CSBM1 and the CSBM2 success rates
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statistically significantly higher in the active arm compared to the control. Similar results were also found in the PP and ITT analysis sets.
| Treatment | Control | |||||
|---|---|---|---|---|---|---|
| % (n/N) | 97.5% CI(Wilson Score) | % (n/N) | 97.5% CI(Wilson Score) | p-value(chi-square) | ||
| mITT | Improve by ≥ 1 CSBM,6 out of 8 weeks | 40.51%(64/158) | [32.18%;49.42%] | 22.92%(33/144) | [16.06%;31.60%] | 0.0011 |
| Improve by ≥ 2 CSBM,6 out of 8 weeks | 23.42%(37/158) | [16.76%;31.72%] | 11.81%(17/144) | [7.03%;19.16%] | 0.0085 | |
| PP | Improve by ≥ 1 CSBM,6 out of 8 weeks | 40.65%(63/155) | [32.23%;49.65%] | 22.92%(33/144) | [16.06%;31.60%] | 0.0010 |
| Improve by ≥ 2 CSBM,6 out of 8 weeks | 23.23%(36/155) | [16.54%;31.60%] | 11.81%(17/144) | [7.03%;19.16%] | 0.0098 | |
| ITT | Improve by ≥ 1 CSBM,6 out of 8 weeks | 39.26%(64/163) | [31.13%;48.04%] | 22.15%(33/149) | [15.50%;30.61%] | 0.0011 |
| Improve by ≥ 2 CSBM,6 out of 8 weeks | 22.70%(37/163) | [16.23%;30.80%] | 11.41%(17/149) | [6.79%;18.55%] | 0.0085 |
Table 4: CSBM1 and CSBM2 Success Rates in mITT, ITT, and PP Analysis Sets
Secondary endpoints
There was an observed reduction in straining in the active arm compared to the control arm (Table 5). Staining was measured using a subject reported scale from 0 (no straining) to 10 (unbearable straining).
| Table 5: Change from Baseline in Straining (Adjusted Baseline) | |
|---|---|
| ---------------------------------------------------------------- | -- |
| Adj. Mean | SE | Two-sided 97.5% CI | ||
|---|---|---|---|---|
| mITT | Treatment | -1.78 | 0.15 | [-2.12;-1.44] |
| Control | -1.32 | 0.16 | [-1.68;-0.97] | |
| Diff. (Treatment-Control) | -0.46 | 0.22 | [-0.95;0.03] | |
| PP | Treatment | -1.80 | 0.15 | [-2.15;-1.46] |
| Control | -1.33 | 0.16 | [-1.69;-0.98] | |
| Diff. (Treatment-Control) | -0.47 | 0.22 | [-0.96;0.02] | |
| ITT | Treatment | -1.71 | 0.15 | [-2.04;-1.37] |
| Control | -1.29 | 0.16 | [-1.65;-0.94] | |
| Diff. (Treatment-Control) | -0.41 | 0.22 | [-0.90;0.08] |
There was an observed improvement in stool consistency (rated using the Bristol Stool scale) in the active arm compared to the control arm (Table 6).
| Table 6: Change from Baseline in Stool Consistency (Adjusted for Baseline) | |
|---|---|
| ---------------------------------------------------------------------------- | -- |
| Adj. Mean | SE | Two-sided 97.5% CI | ||
|---|---|---|---|---|
| mITT | Treatment | 1.03 | 0.08 | [0.85;1.21] |
| mITT | Control | 0.58 | 0.08 | [0.39;0.76] |
| mITT | Diff. (Treatment-Control) | 0.45 | 0.11 | [0.19;0.71] |
| PP | Treatment | 1.02 | 0.08 | [0.84;1.20] |
| PP | Control | 0.58 | 0.08 | [0.40;0.77] |
| PP | Diff. (Treatment-Control) | 0.44 | 0.12 | [0.18;0.70] |
| ITT | Treatment | 0.99 | 0.08 | [0.81;1.16] |
| ITT | Control | 0.57 | 0.08 | [0.38;0.75] |
| ITT | Diff. (Treatment-Control) | 0.42 | 0.11 | [0.16;0.68] |
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No difference was observed in the bloating sensation endpoint (Table 7). Bloating was measured using a subject reported scale from 0 (no bloating) to 10 (unbearable bloating).
| Adj. Mean | SE | Two-sided 97.5% CI | ||
|---|---|---|---|---|
| mITT | Treatment | -0.42 | 0.11 | [-0.67;-0.17] |
| Control | -0.37 | 0.12 | [-0.63;-0.10] | |
| Diff. (Treatment-Control) | -0.06 | 0.16 | [-0.42;0.30] | |
| PP | Treatment | -0.44 | 0.11 | [-0.70;-0.19] |
| Control | -0.37 | 0.12 | [-0.63;-0.11] | |
| Diff. (Treatment-Control) | -0.08 | 0.16 | [-0.44;0.29] | |
| ITT | Treatment | -0.40 | 0.11 | [-0.64;-0.15] |
| Control | -0.36 | 0.11 | [-0.62;-0.10] | |
| Diff. (Treatment-Control) | -0.04 | 0.16 | [-0.39;0.32] |
Table 7: Change from Baseline in Bloating Sensation (Adjusted for Baseline)
Safety results
The ITT data analysis set served as the principal set for the safety analysis: 200 treatment subjects (37 from Active Mode 2 arm and 163 from Active Mode 1 arm) and 149 control subjects. A total of 114 AEs were reported during the study: 74 AEs experienced by 62 treatment subjects (31.0%), and 40 AEs experienced by 26 subjects (17.45%) in the control arm. Two AEs, both in the control arm, were classified as serious adverse events (SAEs), but were not considered related to the study treatment. There were no SAEs reported in the treatment arms.
49 AEs were considered possibly, probably, or definitely related to the study treatment or procedure (41 in the treatment arm, and 8 in the control arm) by study investigators (Table 8), Device and procedure related AEs reported in the study included abdominal pain, abdominal distension, abdominal discomfort, vomiting, nausea, diarrhea, flatulence, and proctalgia (rectal spasm or cramp). Medical device discomfort events characterized as sensation of vibration were the most commonly reported device related AE, with 19 subjects (9.5%) in the Active Mode 1 and 2 treatment arms reporting 21 events (none in the control).
Table 8: Related adverse events that are possibly, or definitely related to the study treatment or procedure, by system organ class, preferred term and relationship (ITT)
| System OrganClass | Preferred Term | Relation to Device | Treatment(Active Modes 1 and 2) | Control | ||||
|---|---|---|---|---|---|---|---|---|
| # ofreports | # ofsubjects | Incidence | # ofreports | # ofsubjects | Incidence | |||
| Total | Total | Total | 41 | 29 | 14.50% | 8 | 5 | 3.36% |
| Possibly related | 12 | 7 | 3.50% | 7 | 4 | 2.68% | ||
| Probably related | 8 | 6 | 3.00% | 1 | 1 | 0.67% | ||
| Related | 18 | 15 | 7.50% | - | - | - | ||
| Related toprocedure | 3 | 2 | 1.00% | - | - | - | ||
| Gastrointestinal | Total | Possibly related | 9 | 5 | 2.50% | 7 | 4 | 2.68% |
| disorders | Probably related | 5 | 5 | 2.50% | 1 | 1 | 0.67% | |
| Abdominal pain | Possibly related | 1 | 1 | 0.50% | 2 | 2 | 1.34% | |
| Vomiting | Possibly related | 3 | 3 | 1.50% | ||||
| Nausea | Possibly related | 1 | 1 | 0.50% | ||||
| Probably related | 1 | 1 | 0.50% | |||||
| Diarrhoea | Possibly related | 1 | 1 | 0.50% | ||||
| Probably related | 1 | 1 | 0.50% | |||||
| Abdominaldistension | Possibly related | 1 | 1 | 0.50% | 1 | 1 | 0.67% | |
| Flatulence | Possibly related | 1 | 1 | 0.50% | ||||
| Constipation | Possibly related | 1 | 1 | 0.50% | ||||
| Proctalgia | Possibly related | 1 | 1 | 0.67% | ||||
| Probably related | 1 | 1 | 0.50% | |||||
| Abdominaldiscomfort | Probably related | 2 | 2 | 1.00% | ||||
| Anorectaldiscomfort | Possibly related | 2 | 1 | 0.67% | ||||
| Abdominallower | pain Possibly related | 1 | 1 | 0.67% | ||||
| Abdominalupper | pain Probably related | 1 | 1 | 0.67% | ||||
| General disorders | Total | Possibly related | 1 | 1 | 0.50% | |||
| and administration | Probably related | 3 | 3 | 1.50% | ||||
| site conditions | Related | 16 | 14 | 7.00% | ||||
| Related toprocedure | 2 | 1 | 0.50% | |||||
| Medical | device Possibly related | 1 | 0.50% | |||||
| discomfort | Probably related | 3 | 3 | 1.50% | ||||
| Related | 16 | 14 | 7.00% | |||||
| Related toprocedure | 1 | 1 | 0.50% | |||||
| Discomfort | Related toprocedure | 1 | 1 | 0.50% | ||||
| Reproductive | Total | Possibly related | 1 | 1 | 0.50% | |||
| system and breastdisorders | Amenorrhoea | Possibly related | 1 | 1 | 0.50% | |||
| Nervous system | Total | Possibly related | 1 | 1 | 0.50% | |||
| disorders | Headache | Possibly related | 1 | 1 | 0.50% | |||
| Psychiatric | Total | Related | 1 | 1 | 0.50% | |||
| disorders | Sleep disorder | Related | 1 | 1 | 0.50% | |||
| Total | Related | 1 | 1 | 0.50% | ||||
| Injury, poisoningand proceduralcomplications | Intentional devicemisuse | Related | 1 | 1 | 0.50% | . | . | . |
| Investigations | Total | Related toprocedure | 1 | 1 | 0.50% | . | . | . |
| Weight decreased | Related toprocedure | 1 | 1 | 0.50% | . | . | . |
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De Novo Summary (DEN210052)
Page 10 of 15
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ADDITIONAL CLINICAL INFORMATION
Five smaller clinical trials were conducted prior to the V270 pivotal study. The studies included a total of 499 subjects and varied from the V270 study treatment protocol in the dosing regimen, number of capsule vibration sets while passing through the large intestine, and/or the number of capsule administered per week. The prior studies do not support effectiveness of the Vibrant System. However, FDA considered the cumulative safety data in these studies to support safety of the Vibrant System. Safety data from these prior studies are consistent in the type, severity and frequency of adverse events reported in the V270 pivotal study.
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.
LABELING
Physician labeling includes the device indications for use, a description of the device, warnings and precautions, clinical data on the device, and instructions for the safe and effective use of the device. The labeling satisfies the requirements of 21 CFR 801.109 Prescription devices. Per the Special Controls for this generic type of device, labeling includes a summary of device effectiveness and device related adverse events.
RISKS TO HEALTH
Table 9 identifies the risks to health that may be associated with use of an orally ingested transient device for constipation, and the measures necessary to mitigate these risks.
| Identified Risks to Health | Mitigation Measures |
|---|---|
| Infection | Bioburden testingLabelingShelf life testing |
| Adverse tissue reaction | Biocompatibility evaluation |
| Device malfunction leading to injury | Electrical safety testingSoftware validation, verification, and hazard analysisNon-clinical performance testingLabelingShelf life testing |
| Interference with other devices | Electromagnetic compatibility testing |
| Failure to excrete capsule | Clinical data |
Table 9 Identified Risks to Health and Mitigation Measures
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| Labeling | |
|---|---|
| Device related adverse events including:• Choking• Abdominal pain• Abdominal distension• Abdominal discomfort• Vomiting• Nausea• Proctalgia• Diarrhea | Clinical dataNon-clinical performance testingLabeling |
| Device ineffective leading to constipation and effects of delayed treatment | Clinical dataLabeling |
SPECIAL CONTROLS
In combination with the general controls of the FD&C Act, an orally ingested transient device for constipation is subject to the following special controls:
- Clinical data must demonstrate the device performs as intended and evaluate the following: (1)
- Treatment of constipation; and (i)
- (ii) All adverse events.
- (2) Non-clinical performance data must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be tested:
- Dimensional testing must verify device dimensions; (i)
- (ii) Performance bench testing must verify functional aspects of the device design;
- (iii) Leak testing must verify device integrity under worst case clinical conditions;
- Bite testing must demonstrate that the device can withstand bite forces; (iv)
- (v) pH resistance testing must evaluate integrity of the capsule when exposed to a physiological relevant range of pH values; and
- Bioburden testing must demonstrate the device does not pose an infection risk (vi) throughout the labeled shelf life.
- The patient-contacting components of the device must be demonstrated to be (3) biocompatible.
- Performance data must support the shelf life of the device by demonstrating continued (4) package integrity and device functionality over the labeled shelf life.
- (5) Software validation, verification, and hazard analysis must be performed.
- Electrical safety and electromagnetic compatibility (EMC) testing must be performed for (6) any electrical components of the device.
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- (7) Labeling for the device must include:
- (i) A summary of clinical data for the device, including a discussion of adverse events and clinical benefit: and
- (ii) A shelf life.
BENEFIT-RISK DETERMINATION
Nonclinical laboratory studies as well as clinical data from a pivotal study (V270) and prior studies were used to evaluate the safety and effectiveness of the Vibrant System.
Summary of Benefits
The V270 pivotal study demonstrated a statistically significant and clinically meaningful benefit over the control. The study met both components of the primary endpoint with higher success rates in the treatment arm compared to the control arm. In 6 out of the 8 weeks of the study, 40.51% in the treatment arm had at least one more weekly CSBM, compared to 22.92% in the control arm, a difference of 17.6% (chi-square p-value = 0.0011, mITT, CSBM1). In 6 out of the 8 weeks of the study, 23.42% in the treatment arm had at least two more weekly CSBM, compared to 11.81% in the control arm, a difference of 10% (chi-square p-value = 0.0085, mITT, CSBM2). The improvements in the number of complete spontaneous bowel movements was statistically significant and clinically meaningful when considering an improvement of 1 and 2 bowel movements during at least 6 of the 8 weeks of treatment in a patient population with chronic idiopathic constipation who have not experienced relief of bowel symptoms by using laxative therapies at the recommended dosage for at least one month.
Factors that increase uncertainty in determining probable benefits for the Vibrant Systems include:
- Inconsistent or conflicting results between studies. Five clinical trials were conducted prior . to the V270 pivotal studies included a total of 499 subjects and varied from the V270 study treatment protocol in the dosing regimen, number of capsule vibration sets while passing through the large intestine, and/or the number of capsule administered per week. The prior studies did not support effectiveness of the Vibrant System.
- . The effectiveness endpoint required an increase of at least one weekly complete spontaneous bowel movement (CSBM) during at least 6 of the 8 weeks of treatment. The study met the primary effectiveness endpoint; however, effectiveness in the CSBM1 treatment arm was 40.5% indicating the response to the Vibrant capsule treatment was not experienced by 59.5% of the treated subjects.
- · The long-term effectiveness of the device has not been studied beyond 8 weeks.
Summary of Risks
A total of 114 AEs were reported during the study. Two AEs were classified as serious adverse events (SAEs) in the control arm that were not considered to the study treatment. There were no SAEs reported in the treatment arms. 49 AEs were considered possibly, or definitely related to the study treatment or procedure (41 in the treatment arm, and 8 in the control arm). Device and procedure related adverse events reported in the study included abdominal pain, abdominal distension, abdominal discomfort, vomiting, nausea, diarrhea,
De Novo Summary (DEN210052)
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flatulence, and proctalgia. Medical device discomfort events characterized as sensation of vibration were the most commonly reported device related AE, with 19 subjects (9.5%) in the Active Mode 1 and 2 treatment arms reporting 21 events (none in the control).
Factors that increase uncertainty in determining probable risks for the Vibrant System include:
- . Insufficient patient numbers to detect less common serious events.
- . Insufficient duration of follow-up to detect delayed/late events. The long-term risks associated with continued repeat use of the device beyond 8 weeks are unknown. The pivotal study collected safety data for 8 weeks.
- . The V270 pivotal study did not include evaluation for capsule retrievals once they passed through the GI tract. An earlier safety study (V11) evaluated capsule retrieval directly in a 28 subject safety study and reported a capsule retrieval rate of 85%; however, subjects in the V111 study had difficulty identifying the capsules in bowel movements.
Patient Perspectives
Patient perspectives were measured in the V270 trial as an additional endpoint assessment. Treatment Satisfaction Questionnaire for Medication (TSQM) scores were evaluated in the V270 study. The TSOM score for effectiveness was reported to be higher in the treatment arm relative to the control arm. The mean scores for side-effects, convenience, and global satisfaction were similar in both groups.
Change from baseline in quality of life using the Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL) questionnaire2 was evaluated in the V270 study. More subjects reported an improvement in quality of life from baseline on the PAC-OOL in the active arm 1 than in the control arm (77.9% of active arm 1 subjects versus 66.2% of control arm subjects).
Benefit/Risk Conclusion
The V270 pivotal study reports a statistically significant and clinically meaningful clinical benefit for the Vibrant System treatment of chronic idiopathic constipation with an improvement in the number of complete spontaneous bowel movements per week over an 8-week treatment course. Considering the types, numbers, and mild-to-moderate severity of adverse events in the treatment arm compared to the control arm, there is an overall favorable benefit-risk profile that supports granting this De Novo request.
1 Atkinson MJ, Sinha A, Hass SL, Colman SS, Kumar RN, Brod M, Rowland CR. Validation of a general measure of treatment satisfaction, the Treatment Satisfaction (TSOM), using a national panel study of chronic disease. Health Qual Life Outcomes. 2004 Feb 26;2:12. doi: 10.1186/1477-7525-2-12. PMID: 14987333; PMCID: PMC398419.
2 Marquis P. De La Loge C. Dubois D. McDermott A. Chassany O. Development and validation of the Patient Assessment of Constipation Quality of Life questionnaire. Scand J Gastroenterol. 2005 May:40(5):540-51. doi: 10.1080/00365520510012208. PMID: 16036506.
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In conclusion, given the available information above, the probable benefits outweigh the probable risks for the Vibrant System when used as indicated. The device provides benefits, and the risks can be mitigated using general controls and the identified special controls.
CONCLUSION
The De Novo request for the Vibrant System is granted and the device is classified as follows:
Product Code: QTN Device Type: Orally ingested transient device for constipation Regulation Number: 21 CFR 876.5940 Class: II
N/A