PROTEUS INGESTION CONFINMATION SYSTEMS

DEN120011 · Proteus Biomedical, Inc. · OZW · Jul 10, 2012 · General Hospital

Device Facts

• Record ID: DEN120011
• Device Name: PROTEUS INGESTION CONFINMATION SYSTEMS
• Applicant: Proteus Biomedical, Inc.
• Product Code: OZW · General Hospital
• Decision Date: Jul 10, 2012
• Decision: DENG
• Submission Type: Post-NSE
• Regulation: 21 CFR 880.6305
• Device Class: Class 2

Indications for Use

The Proteus Personal Monitor is a miniaturized, wearable data-logger for ambulatory recording of heart rate, activity, body angle relative to gravity, and time-stamped, patientlogged events, including events signaled by swallowing the Ingestion Event Marker (IEM) accessory. The Proteus Personal Monitor enables unattended data collection for clinical and research applications. The Proteus Personal Monitor may be used in any instance where quantiffable analysis of event-associated heart rate, activity, and body position is desirable.

Device Story

System comprises ingestible event marker (IEM), wearable patch, and mobile software. IEM is grain-of-sand sized sensor attached to inert excipient tablet; swallowed by patient. Upon ingestion, IEM communicates via volume conduction (intrabody communication) to wearable patch. Patch collects physiological data (heart rate, activity, body angle) and logs ingestion events. Patch stores and wirelessly transmits data to mobile computing device. Software organizes and displays ingestion events for clinician/researcher review. Used in ambulatory settings; enables unattended data collection. Output allows providers to correlate medication ingestion with physiological/behavioral metrics, potentially improving adherence monitoring and clinical decision-making.

Clinical Evidence

Clinical data from 254 subjects over 3,811 subject-days and 11,655 ingestions. Primary endpoints: Positive Detection Accuracy (PDA) and Negative Detection Accuracy (NDA). Cumulative PDA 97.2% (95% CI); cumulative NDA 100% (95% CI). Safety profile: No unanticipated adverse device effects or severe adverse events related to the system. Minor skin irritation reported with patch use.

Technological Characteristics

System includes ingestible sensor (IEM) and wearable patch. IEM uses volume conduction (intrabody communication). Patch includes accelerometer for activity/body angle and ECG sensors. Biocompatibility per ISO 10993-5, -10, -11. Electrical safety per IEC 60601-1; EMC per IEC 60601-1-2. Patch is internally powered. Software organizes/displays data on mobile devices.

Indications for Use

Indicated for ambulatory patients requiring monitoring of heart rate, activity, body angle, and time-stamped ingestion events. Used for clinical and research applications where quantifiable analysis of event-associated physiological and behavioral metrics is required.

Regulatory Classification

Identification

An ingestible event marker is a prescription device used to record time-stamped, patient-logged events. The ingestible component links wirelessly through intrabody communication to an external recorder which records the date and time of ingestion as well as the unique serial number of the ingestible device.

Special Controls

In combination with the general controls of the FD&C Act, the Proteus Personal Monitor including Ingestion Event Marker is subject to the following special controls:

*Classification.* Class II (special controls). The special controls for this device are:(1) The device must be demonstrated to be biocompatible and non-toxic; (2) Nonclinical, animal, and clinical testing must provide a reasonable assurance of safety and effectiveness, including device performance, durability, compatibility, usability (human factors testing), event recording, and proper excretion of the device; (3) Appropriate analysis and nonclinical testing must validate electromagnetic compatibility performance, wireless performance, and electrical safety; and (4) Labeling must include a detailed summary of the nonclinical and clinical testing pertinent to use of the device and the maximum number of daily device ingestions.

Reference Devices

• Proteus Personal Monitor (K093976)

Submission Summary (Full Text)

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#### EVALUATION OF AUTOMATIC CLASS III DESIGNATION (DE NOVO) FOR PROTEUS PERSONAL MONITOR INCLUDING INGESTION EVENT MARKER

#### REGULATORY INFORMATION

FDA identifies this generic type of device as:

Ingestible Event Marker - An ingestible event marker is a prescription device used to record time-stamped, patient-logged events. The ingestible component links wirelessly through intra-body communication to an external recorder which records the date and time of ingestion as well as the unique serial number of the ingestible device.

#### NEW REGULATION NUMBER: 880.6305

CLASSIFICATION: II

PRODUCT CODE: OZW

#### BACKGROUND

## DEVICE NAME: PROTEUS PERSONAL MONITOR INCLUDING INGESTION EVENT MARKER

510(K): K113070

DATE OF 510(K) NSE DECISION: MAY 7, 2012

DATE OF DE NOVO PETITION: MAY 14, 2012

PETITIONER CONTACT: PROTEUS BIOMEDICAL, INC. 2600 BRIDGE PARKWAY, SUITE 101 REDWOOD CITY, CA 94065 Phone: [phone] Fax: [phone]

#### PETITIONER'S RECOMMENDED CLASSIFICATION: II

#### INDICATIONS FOR USE

The Proteus Personal Monitor is a miniaturized, wearable data-logger for ambulatory recording of heart rate, activity, body angle relative to gravity, and time-stamped, patientlogged events, including events signaled by swallowing the Ingestion Event Marker (IEM) accessory. The Proteus Personal Monitor enables unattended data collection for clinical and research applications. The Proteus Personal Monitor may be used in any instance where quantiffable analysis of event-associated heart rate, activity, and body position is desirable.

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# LIMITATIONS

Prescription-use only

Caution: Do not wear (the Patch) during magnetic resonance imaging (MRI), cautery, and external defibrillation procedures.

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

## DEVICE DESCRIPTION

The Proteus Personal Monitor, also called the "Patch", is a body-worn sensor that collects physiological and behavioral metrics including heart rate, activity, body angle and time-stamped user-logged events generated when a user marks an event by swallowing an Ingestion Event Marker (IEM) or by manually pressing an event marker button on the Patch. The Patch stores and wirelessly sends the IEM data to a general computing device.

The Proteus Personal Monitor Ingestion Event Marker system is comprised of three main subsystems; (1) the ingestion event marker (IEM), (2) the data recorder (Patch), and (3) the Proteus software.

- 1. Ingestion Event Marker (IEM)
The grain-of-sand sized IEM is designed to communicate the time-stamped confirmation of IEM device ingestion as a unique identifier to the Proteus Personal Monitor worn on the skin. The ingestion signal is communicated via volume conduction communication also known as intrabody communication. The IEM is attached to an inert pharmaceutical excipient tablet for ease of handling and swallowability.

2. Proteus Personal Monitor (Patch)

The Proteus Personal Monitor (Patch) receives, stores, and wirelessly sends ingestion confirmation data to a general computing device.

## 3. Software

The Proteus software is used to pair the Patch with a mobile computing device. The software organizes and displays ingestion events.

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Image /page/2/Picture/0 description: The image shows a diagram of a Proteus Personal Monitor (PPM) and an Ingestible Event Marker (IEM). The PPM is a small, wearable sensor that is placed on the skin. The IEM is a small, ingestible sensor that is swallowed. The IEM sends a signal to the PPM when it is ingested. The PPM then records the time and date of ingestion.

Figure 1: An overview of the Proteus Personal Monitor System - IEM (attached to an inert tablet carrier) and Patch, plus a display screen on a paired computing device (not pictured). Magnified view of IEM with attached excipient skirt is also displayed in graphic.

# SUMMARY OF NONCLINICAL/BENCH STUDIES

# BIOCOMPATIBILITY/MATERIALS (IEM)

The petitioner conducted a series of tests to demonstrate that the patient-contacting components of the Proteus Personal Monitor demonstrated acceptable performance for its intended purpose, which included the tests indicated below.

ISO 10993-5 CYTOTOXICITY TESTING ISO 10993-10 IRRITATION TESTING ISO 10993-11 SYSTEMIC TOXICITY TESTING

Given the results of the biocompatibility testing, the petitioner conducted additional animal testing to assess materials toxicity, which included the following tests summarized in Table 1 below.

| | Testing Performed | Results |
|------------------------------|-----------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------|
| Chemical<br>Characterization | HPLC And Spectroscopic<br>Analysis Of Concentrated<br>Device Extracts | No Unintended Compounds<br>Detected Above Stringent ICH<br>Reporting Threshold For Drug<br>Impurities |
| Copper (Cu)<br>Toxicity | Risk Assessment By<br>Gradient Corp (Metal<br>Toxicology Experts) | No Risk Of Cu Toxicity With<br>Realistic Exposure |
| Cytotoxicity | Quantitative Studies With<br>Physiologic Device Extracts | Realistic Exposure Levels Are<br>Non-Cytotoxic |

TABLE 1. PRE-CLINICAL SAFETY TESTING

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# IN VIVO STUDIES

The petitioner also performed forty-two (42) in-vivo studies, including rodent, canine and porcine models, to characterize device performance and safety. Porcine and canine animal models are frequently used in gastrointestinal (GI) device testing, and were chosen because of the similarities of their GI anatomy to that of a human. Efforts were made to include a wide range of body size in the non-clinical experiments, with body weight ranging from 25 to 95 kg. The purpose of this inclusion criterion is to provide an opportunity to investigate the potential effects of body size on the performance of the system. Canine testing was also performed to validate that device egestion occurred as well as additional rodent testing and literature review to assess toxicology of materials. A summary of the studies conducted are provided in Table 2.

| | Testing Performed | Results |
|-------------------|---------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Mechanical safety | Excretion and GI injury studies in canines | Ingested IEMs reliably excreted<br>Supra-normal doses of IEMs do not inflict<br>any clinically significant injuries |
| Electrical safety | Tissue stimulation in canines | No abnormal ECG morphology or<br>arrhythmia |
| In vivo toxicity | 14-day rat oral gavage study with physiologic device extracts | No evidence of toxicity in any dosing<br>groups, including max dose group<br>(equivalent to 30,000 IEMs/day), based<br>upon clinical observations, hematology,<br>serum chemistries and histopathology. |
| | Canine oral toxicology study | No evidence of IEM toxicity, based upon<br>clinical observations and GI tract<br>histopathology. No changes in blood<br>levels of IEM inorganic materials<br>following exposure. |
| | Rodent oral toxicology study | No evidence of IEM toxicity—even in<br>highest dosing group, which received the<br>weight-adjusted equivalent of 30,000<br>IEMs/day—based upon clinical<br>observations, hematology, coagulation<br>tests, blood chemistries, necropsy, and<br>comprehensive histopathology. |
| | IEM copper (Cu) human<br>health assessment, general<br>use | Practical-use scenario (15 IEMs ingested<br>simultaneously, daily or twice-daily)<br>poses no risk of copper toxicity. Extreme-<br>use scenario (30 IEMs ingested<br>simultaneously, daily) poses no risk of<br>systemic toxicity, but transient, non-<br>systemic gastric upset could result at this<br>dose. This concentration dependent effect |

# TABLE 2. PERFORMANCE AND SAFETY TESTING

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| IEM copper human health<br>assessment, chronic use in<br>a compromised population<br>(renal transplant patients) | would be mitigated by intake with a meal.<br>Post-operative renal transplant patients are<br>not at greater risk than the normal<br>population from Cu toxicity associated<br>with chronic ingestion of four IEMs/day.<br>There is no scientific basis to believe that<br>the physiological response to Cu in IEM-<br>enabled medicines will differ from the<br>physiological response to Cu in food. |
|------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Quantitative cytotoxicity | Corroborates conclusion of IEM Cu<br>human health assessment. |
| Additional chemical<br>characterizations | No unintended compounds detected above<br>reporting threshold for new drug<br>substances, a stringent standard that was<br>adapted for analysis of the IEM device. |

# ELECTROMAGNETIC COMPATIBILITY (EMC) AND ELECTRICAL SAFETY

Electromagnetic compatibility and electrical safety testing were performed to FDA recognized standards. All applicable tests passed.

| Testing<br>Category | Test Descriptions | Reference | Results |
|------------------------------|---------------------------------------------------------------------------|---------------------------------------|-----------------------------------------------------------------------------------------------------------|
| Electrical<br>safety testing | Power input | IEC 60601-1, Sub-<br>clause 7.1 | Not applicable,<br>because the unit is<br>internally powered |
| | Limitation of voltage<br>and/or energy | IEC 60601-1, Sub-<br>clause 15 b | Not applicable,<br>because the unit is<br>internally powered |
| | Protective earthing,<br>functional earthing and<br>potential equalization | IEC 60601-1, Sub-<br>clause 18 f | Not applicable,<br>because the unit is<br>internally powered<br>and has a non-<br>conductive<br>enclosure |
| | Earth leakage current | IEC 60601-1, Sub-<br>clause 19.4 f | Not applicable,<br>because the unit is<br>internally powered |
| | Enclosure leakage<br>current | IEC 60601-1, Sub-<br>clause 19.4 g | Not applicable,<br>because the unit is<br>internally powered<br>and has a non-<br>conductive<br>enclosure |
| | Patient leakage current | IEC 60601-1, Sub-<br>clause 19.4 h, 6 | Passed, 0 μA<br>measured |

TABLE 3. EMC AND ELECTRICAL SAFETY TESTING

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| | Patient leakage with<br>mains voltage on F-<br>type isolated applied<br>parts | IEC 60601-1, Sub-clause 19.4 h.6 | Passed, 0 $\u03bc$ A r.m.s measured |
|--------------------|-------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------|
| | Patient auxiliary<br>current | IEC 60601-1, Sub-clause 19.4 j | Passed, maximum<br>of < $1$ $\u03bc$ A r.m.s measured |
| | Dielectric voltage<br>withstand | IEC 60601-1, Sub-clause 20.4 | Passed |
| | Reversed battery<br>connection | IEC 60601-1, Sub-clause 56.7 | Not applicable;<br>battery is not user-accessible |
| | Overflow, spillage,<br>leakage, cleaning | IEC 60601-1, Sub-clause 44 | Passed |
| | Creepage distances and<br>air clearances | IEC 60601-1, Sub-clause 57.10 | Passed |
| EMC testing | Group 1 Class B –<br>Radiated emissions | per EN 60601-1-2,<br>EN 55011 (CISPR<br>11) | Passed |
| IEM EMC<br>testing | Electromagnetic<br>compatibility (EMC) | IEC 60601-1-2:2007<br>6.2.3 Radiated RF<br>electromagnetic<br>fields Part 4-3:<br>Testing and<br>measurement<br>techniques –<br>Radiated, radio-<br>frequency,<br>electromagnetic field<br>immunity test | Passed |

# ADDITIONAL DEVICE CHARACTERIZATION AND PERFORMANCE TESTING

The sponsor performed testing to characterize the performance of the ingestible disc antenna used in the IEM (Table 4) and simulation testing signal reception performance of the Patch data recorder (Table 5).

TABLE 4. INGESTIBLE DISC ANTENNA TESTING

| Test Description | Result |
|------------------------------------------------------------------|--------|
| Mechanical strength - immersion in SGF<br>for 10 minutes at 37°C | (b) (4 |
| Residual solvent of the disc material | |
| Friability - immersion in SGF (10 mins)<br>then SIF at 37°C | |
| Electrical properties of disc | |

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| Test | Test Description | Result |
|---------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| High Frequency (HF)<br>Signal Chain<br>Performance Test | A “body simulation” network was<br>interposed between the signal<br>source and the Data Recorder | The passband is<br>substantially flat<br>between 10Hz and<br>80Hz |
| Low Frequency (LF)<br>Signal Chain<br>Performance Test | A patient simulator was attached<br>to the inputs and the amplitude of<br>the output was measured by an<br>oscilloscope | The passband is<br>substantially flat<br>between 2Hz and<br>100Hz |
| Accelerometer<br>Performance Tests | Rotating the accelerometer with<br>respect to gravity<br>--<br>Acceleration measurement from a<br>subject during a steady walk | Measured values<br>agreed well with the<br>applied values R2<br>=.99<br>--<br>The acceleration<br>traces appear to be of<br>a subject walking. |
| ECG Performance<br>Testing | The algorithm was tested against<br>all 48 test files from the MIT-BIH<br>arrhythmia database.<br>--<br>The PROMITTER substudy was<br>conducted on the Proteus campus<br>and enrolled 5 healthy volunteer<br>subjects | The Median was<br>99.7% detection with<br>a 5.9% standard<br>deviation<br>--<br>ECG results and<br>accuracy was 99.4%<br>for chest location and<br>99.2% for xyphoid<br>location |
| Respiratory Rate<br>Performance Testing | R-wave amplitude is modulated by<br>the respiratory cycle, a stationary<br>subject was instructed to breath<br>regularly at a rate of 6 breaths/min | Device measurement<br>result of 6<br>breaths/minute |

TABLE 5. DATA RECORDER TESTING

## MAGNETIC RESONANCE (MR) COMPATIBILITY

No testing has been conducted to demonstrate whether the device is MR compatible. The labeling has included a Caution that the user should not wear the Patch during magnetic resonance imaging (MRI).

## SOFTWARE

The petitioner provided a description of software development processes, software hazard analysis and device system performance testing. The Patch software was reviewed in K093976 in conformance with FDA's Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices, May 11, 2005.

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# SUMMARY OF CLINICAL INFORMATION

The Proteus system has been used by > 250 patients who participated in >3,800 cumulative days of system use involving >11,500 cumulative IEM ingestions as summarized in Tables 6 and 7 below. The studies characterized the safety and performance of the Proteus system. The safety of the system was characterized by recording all patient adverse events (AEs) noted during the study whether device related or not. The key measures of system performance (positive detection accuracy (PDA) and negative detection accuracy (NDA)) characterize the ability of the system to properly detect and register IEM ingestions.

The cumulative average of PDA across all conducted studies is 97.2% (95% CI). The cumulative average of NDA across all conducted studies is 100% (95% CI).

| TABLE 6. RESULTS OF HUMAN CLINICAL TESTING | | | |
|----------------------------------------------------------------------------------------------------------------------------------------|--------|-----------------------------|-------------------------------|
| Cumulative Clinical Experience | N | | |
| Number of subjects wearing the<br>Proteus Personal Monitor (Patch) | 254 | | |
| Number of subjects ingesting IEM | 219 | | |
| Number of subject/days | 3,811 | | |
| Number of IEM ingestions | 11,655 | | |
| No unanticipated adverse device effects, no severe adverse events<br>related to or possibly related to Proteus Personal Monitor System | | | |
| Non-serious AEs--92% mild, 8%<br>moderate | | | |
| Adverse Event (AE) – Ingestible<br>Sensor | | Rate as<br>% of<br>subjects | Rate as %<br>of<br>ingestions |
| At least one AE | 0 | 0 | 0 |
| At least one severe AE | 0 | 0 | 0 |
| Discontinued due to AE | 0 | 0 | 0 |
| Adverse Events | | | |
| Nausea/vomiting | 4 | 1.8% | 0.0% |
| Related | 1 | 0.5% | 0.0% |
| Constipation | 2 | 0.9% | 0.0% |
| Anxiety | 1 | 0.5% | 0.0% |
| Asthma attack | 1 | 0.5% | 0.0% |
| Abdominal cramping | 1 | 0.5% | 0.0% |
| Non-cardiac chest pain | 1 | 0.5% | 0.0% |
| Bitter taste in mouth | 1 | 0.5% | 0.0% |
| Adverse Event – PPM (510(k)<br>cleared component) | | | |
| Localized skin irritation and<br>inflammation | 45 | 17.7% | NA |
| Discontinued due to skin irritation | 7 | 2.8% | NA |

TABLE 6. RESULTS OF HUMAN CLINICAL TESTING

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# TABLE 7. SUMMARY OF HUMAN CLINICAL TESTING

| Overall System Performance | |
|---------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------|
| 219 subjects of 254 subjects,<br>inclusive of PPM-only users (IEM<br>ingestion) | 99.3% Detection accuracy<br>100% Correct identification<br>No SAEs / UADEs related to system |
| 11,655 ingestions | |
| 3810 subject-days of system<br>utilization | |
| Maximum daily ingestion: 34 IEMs | |
| Maximum system utilization: 42<br>days | |

# LABELING

Labeling includes all information required for the safe and effective use of the device as outlined in 801.109, including a detailed summary of the non-clinical testing pertinent to use of the device and the maximum number of daily device ingestions.

## RISKS TO HEALTH

Table 8 below identifies the risks to health that may be associated with use of Ingestible Event Markers and the measures recommended to mitigate these risks.

| Identified Risks | Recommended Mitigation Measures |
|---------------------------------|-----------------------------------------------------------------------|
| Adverse tissue reaction | Biocompatibility Testing<br>Labeling (dose limits) |
| Systemic toxicity | Toxicology Testing<br>Labeling (dose limits) |
| Electromagnetic incompatibility | Electromagnetic Compatibility Testing<br>Wireless testing<br>Labeling |
| Electrical safety issues | Electrical Safety Testing<br>Labeling |
| Electrical/Mechanical failure | Non-clinical Performance Testing |
| Failure to mark event | Non-clinical Performance Testing<br>Clinical Evaluation |
| Failure to excrete | Animal Testing |
| Usability | Human Factors Testing<br>Labeling |

Table 8 Risk/Mitigation Measures

# SPECIAL CONTROLS

In combination with the general controls of the FD&C Act, the Proteus Personal Monitor including Ingestion Event Marker is subject to the following special controls:

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- 1. The device must be demonstrated to be biocompatible and non-toxic;
- 2. Non-clinical, animal and clinical testing must provide a reasonable assurance of safety and effectiveness, including device performance, durability, compatibility, usability (human factors testing), event recording, and proper excretion of the device;
- 3. Appropriate analysis and non-clinical testing must validate electromagnetic compatibility (EMC) performance, wireless performance, and electrical safety; and
- 4. Labeling must include a detailed summary of the non-clinical and clinical testing pertinent to use of the device and the maximum number of daily device ingestions.

#### BENEFIT/RISK DETERMINATION

The Benefit/Risk Determination for the Proteus Personal Monitor finds that although the benefits realized by the use of the device system are small, the risks posed by the device system are also small and pose little to no risk to the patient when Special Controls are met and are outweighed by the benefits of the device system.

#### CONCLUSION

The de novo petition for the Proteus Personal Monitor including Ingestion Event Marker is granted and the device is classified under the following:

Product Code: OZW Device Type: Proteus Personal Monitor including Ingestion Event Marker Class: II Regulation: 21 CFR 880.6305