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 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.

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.
Proteus Personal Monitor (Patch)
The Proteus Personal Monitor (Patch) receives, stores, and wirelessly sends ingestion confirmation data to a general computing device.
Software
The Proteus software is used to pair the Patch with a mobile computing device. The software organizes and displays ingestion events.

AI/ML Overview

Here's the breakdown of the acceptance criteria and the study details for the Proteus Personal Monitor including Ingestion Event Marker:

Acceptance Criteria and Device Performance

Acceptance Criteria	Reported Device Performance
Biocompatibility/Non-toxicity: Demonstrate the device is biocompatible and non-toxic.	IEM: - Cytotoxicity: No unintended compounds detected above stringent ICH reporting threshold. Realistic exposure levels are non-cytotoxic. - Copper (Cu) Toxicity: No risk of Cu toxicity with realistic exposure. Realistic exposure levels are non-cytotoxic.
Mechanical Safety (Excretion & GI Injury): Ingested IEMs reliably excreted, and supra-normal doses do not inflict clinically significant injuries.	Canine studies: Ingested IEMs reliably excreted. Supra-normal doses of IEMs do not inflict any clinically significant injuries.
Electrical Safety (Tissue Stimulation, Leakage Current, Dielectric Withstand, etc.): No abnormal ECG morphology or arrhythmia; all applicable electrical safety tests passed.	Canine studies: No abnormal ECG morphology or arrhythmia.
In Vivo Toxicity: No evidence of toxicity even at high doses in relevant animal models.	14-day rat oral gavage study: No evidence of toxicity in any dosing groups, including max dose (equivalent to 30,000 IEMs/day). Canine oral toxicology study: No evidence of IEM toxicity. Rodent oral toxicology study: No evidence of IEM toxicity (even in highest dose group, equivalent of 30,000 IEMs/day). IEM copper (Cu) human health assessment: Practical-use scenario (15 IEMs simultaneously, daily or twice-daily) poses no risk of copper toxicity. Extreme-use scenario (30 IEMs simultaneously, daily) poses no risk of systemic toxicity, but transient, non-systemic gastric upset could result (mitigated by intake with meal). Post-operative renal transplant patients not at greater risk. Physiological response to Cu in IEMs will not differ from Cu in food.
Electromagnetic Compatibility (EMC): All applicable EMC tests passed.	EMC testing (Patch and IEM): Passed EN 60601-1-2, EN 55011 (CISPR 11), and IEC 60601-1-2:2007 6.2.3.
Device Performance (Event Recording): Characterize positive detection accuracy (PDA) and negative detection accuracy (NDA) for IEM ingestions.	Clinical Studies: - Cumulative average Positive Detection Accuracy (PDA): 97.2% (95% CI) - Cumulative average Negative Detection Accuracy (NDA): 100% (95% CI) - Overall System Detection Accuracy: 99.3%
Software: Software development processes, hazard analysis, and system performance testing conform to FDA guidance.	Patch software reviewed in K093976 in conformance with FDA's Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices, May 11, 2005.

Study Information

1. A table of acceptance criteria and the reported device performance:
See table above.

2. Sample size used for the test set and the data provenance:

Human Clinical Test Set:
- Number of subjects: 219 subjects ingested IEMs across multiple studies, with 254 subjects wearing the Proteus Personal Monitor (Patch) in total.
- Number of IEM ingestions: 11,655 cumulative IEM ingestions.
- Subject/days of system use: 3,811 cumulative subject-days.
- Data Provenance: Not explicitly stated, but the mention of "The PROMITTER substudy was conducted on the Proteus campus and enrolled 5 healthy volunteer subjects" suggests some studies were conducted in the US. The overall clinical data likely comes from studies conducted by Proteus Biomedical, Inc. (based in Redwood City, CA). The data appears to be prospective as it involves active participation in clinical trials.
Animal Test Set:
- Number of animals: Forty-two (42) in-vivo studies in rodent, canine, and porcine models. The specific number of animals per study is not detailed.
- Data Provenance: Not explicitly stated, but likely from studies commissioned by Proteus Biomedical, Inc. and conducted in laboratory settings. These are prospective animal studies.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

Clinical Studies (IEM Ingestion Detection): The document does not specify the number of experts or their qualifications for establishing the ground truth of IEM ingestion events in the clinical studies. Typically, this would involve direct observation, patient logs, or other objective measures as the ground truth for "ingestion event" rather than expert interpretation of a signal.
ECG Performance Testing: For the MIT-BIH arrhythmia database, the ground truth is established by cardiologists and is inherent to the database itself. For the PROMITTER substudy, it is not specified how the ECG ground truth was established, but typically this would involve a reference ECG device and interpretation by cardiology experts.

4. Adjudication method for the test set:

The document does not explicitly describe an adjudication method (like 2+1 or 3+1) for disagreement among experts, which typically applies to subjective interpretations. For IEM ingestion events, the ground truth is likely directly observed or logged, rather than relying on interpretation that would require adjudication.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

No, a multi-reader multi-case (MRMC) comparative effectiveness study focusing on human readers improving with or without AI assistance was not conducted or reported in this document. The device's primary function is to automatically detect ingestion events, not to assist human readers in interpreting medical images or other data that typically involves MRMC studies.

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

Yes, the core performance metrics "Positive Detection Accuracy (PDA)" and "Negative Detection Accuracy (NDA)" for IEM ingestion detection represent the standalone (algorithm only) performance of the Proteus Personal Monitor system. The system automatically detects and logs these events without direct human-in-the-loop intervention for each individual ingestion detection.

7. The type of ground truth used:

IEM Ingestion Detection: The ground truth for IEM ingestion events in human clinical studies is implicitly based on documented ingestions by the subjects. This would likely involve patient logs, direct observation during controlled settings, or other objective confirmation of "patient-logged events" as described in the Indications for Use.
Physiological Measurements (ECG, Accelerometer, Respiratory Rate): For these, the ground truth was established using:
- Standard databases: MIT-BIH arrhythmia database for ECG performance.
- Reference measurements: Applied values for accelerometers, controlled breathing rates for respiratory rate.
Safety (Toxicity, Biocompatibility): Ground truth established through established laboratory testing protocols, histopathology, clinical observations, and established toxicology assessments by experts (e.g., Gradient Corp for metal toxicology).

8. The sample size for the training set:

The document does not provide details on the sample size used for training the algorithms. This information is typically proprietary or not included in regulatory summaries focused on validation.

9. How the ground truth for the training set was established:

The document does not provide details on how the ground truth for the training set was established. Similar to the test set, it would likely involve objective data related to IEM ingestion, physiological signals with known parameters, or established clinical diagnoses for specific outcomes targeted by any machine learning components.

Summary

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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: 650-632-4031 Fax: 650-362-1860

PETITIONER'S RECOMMENDED CLASSIFICATION: II

INDICATIONS FOR USE

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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 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.

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
ChemicalCharacterization	HPLC And SpectroscopicAnalysis Of ConcentratedDevice Extracts	No Unintended CompoundsDetected Above Stringent ICHReporting Threshold For DrugImpurities
Copper (Cu)Toxicity	Risk Assessment ByGradient Corp (MetalToxicology Experts)	No Risk Of Cu Toxicity WithRealistic Exposure
Cytotoxicity	Quantitative Studies WithPhysiologic Device Extracts	Realistic Exposure Levels AreNon-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 excretedSupra-normal doses of IEMs do not inflictany clinically significant injuries
Electrical safety	Tissue stimulation in canines	No abnormal ECG morphology orarrhythmia
In vivo toxicity	14-day rat oral gavage study with physiologic device extracts	No evidence of toxicity in any dosinggroups, including max dose group(equivalent to 30,000 IEMs/day), basedupon clinical observations, hematology,serum chemistries and histopathology.
	Canine oral toxicology study	No evidence of IEM toxicity, based uponclinical observations and GI tracthistopathology. No changes in bloodlevels of IEM inorganic materialsfollowing exposure.
	Rodent oral toxicology study	No evidence of IEM toxicity—even inhighest dosing group, which received theweight-adjusted equivalent of 30,000IEMs/day—based upon clinicalobservations, hematology, coagulationtests, blood chemistries, necropsy, andcomprehensive histopathology.
	IEM copper (Cu) humanhealth assessment, generaluse	Practical-use scenario (15 IEMs ingestedsimultaneously, daily or twice-daily)poses no risk of copper toxicity. Extreme-use scenario (30 IEMs ingestedsimultaneously, daily) poses no risk ofsystemic toxicity, but transient, non-systemic gastric upset could result at thisdose. This concentration dependent effect

TABLE 2. PERFORMANCE AND SAFETY TESTING

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IEM copper human healthassessment, chronic use ina compromised population(renal transplant patients)	would be mitigated by intake with a meal.Post-operative renal transplant patients arenot at greater risk than the normalpopulation from Cu toxicity associatedwith chronic ingestion of four IEMs/day.There is no scientific basis to believe thatthe physiological response to Cu in IEM-enabled medicines will differ from thephysiological response to Cu in food.
Quantitative cytotoxicity	Corroborates conclusion of IEM Cuhuman health assessment.
Additional chemicalcharacterizations	No unintended compounds detected abovereporting threshold for new drugsubstances, a stringent standard that wasadapted 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.

TestingCategory	Test Descriptions	Reference	Results
Electricalsafety testing	Power input	IEC 60601-1, Sub-clause 7.1	Not applicable,because the unit isinternally powered
	Limitation of voltageand/or energy	IEC 60601-1, Sub-clause 15 b	Not applicable,because the unit isinternally powered
	Protective earthing,functional earthing andpotential equalization	IEC 60601-1, Sub-clause 18 f	Not applicable,because the unit isinternally poweredand has a non-conductiveenclosure
	Earth leakage current	IEC 60601-1, Sub-clause 19.4 f	Not applicable,because the unit isinternally powered
	Enclosure leakagecurrent	IEC 60601-1, Sub-clause 19.4 g	Not applicable,because the unit isinternally poweredand has a non-conductiveenclosure
	Patient leakage current	IEC 60601-1, Sub-clause 19.4 h, 6	Passed, 0 μAmeasured

TABLE 3. EMC AND ELECTRICAL SAFETY TESTING

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	Patient leakage withmains voltage on F-type isolated appliedparts	IEC 60601-1, Sub-clause 19.4 h.6	Passed, 0 $\u03bc$ A r.m.s measured
	Patient auxiliarycurrent	IEC 60601-1, Sub-clause 19.4 j	Passed, maximumof < $1$ $\u03bc$ A r.m.s measured
	Dielectric voltagewithstand	IEC 60601-1, Sub-clause 20.4	Passed
	Reversed batteryconnection	IEC 60601-1, Sub-clause 56.7	Not applicable;battery is not user-accessible
	Overflow, spillage,leakage, cleaning	IEC 60601-1, Sub-clause 44	Passed
	Creepage distances andair clearances	IEC 60601-1, Sub-clause 57.10	Passed
EMC testing	Group 1 Class B –Radiated emissions	per EN 60601-1-2,EN 55011 (CISPR11)	Passed
IEM EMCtesting	Electromagneticcompatibility (EMC)	IEC 60601-1-2:20076.2.3 Radiated RFelectromagneticfields Part 4-3:Testing andmeasurementtechniques –Radiated, radio-frequency,electromagnetic fieldimmunity 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 SGFfor 10 minutes at 37°C	(b) (4
Residual solvent of the disc material
Friability - immersion in SGF (10 mins)then SIF at 37°C
Electrical properties of disc

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Test	Test Description	Result
High Frequency (HF)Signal ChainPerformance Test	A “body simulation” network wasinterposed between the signalsource and the Data Recorder	The passband issubstantially flatbetween 10Hz and80Hz
Low Frequency (LF)Signal ChainPerformance Test	A patient simulator was attachedto the inputs and the amplitude ofthe output was measured by anoscilloscope	The passband issubstantially flatbetween 2Hz and100Hz
AccelerometerPerformance Tests	Rotating the accelerometer withrespect to gravity--Acceleration measurement from asubject during a steady walk	Measured valuesagreed well with theapplied values R2=.99--The accelerationtraces appear to be ofa subject walking.
ECG PerformanceTesting	The algorithm was tested againstall 48 test files from the MIT-BIHarrhythmia database.--The PROMITTER substudy wasconducted on the Proteus campusand enrolled 5 healthy volunteersubjects	The Median was99.7% detection witha 5.9% standarddeviation--ECG results andaccuracy was 99.4%for chest location and99.2% for xyphoidlocation
Respiratory RatePerformance Testing	R-wave amplitude is modulated bythe respiratory cycle, a stationarysubject was instructed to breathregularly at a rate of 6 breaths/min	Device measurementresult of 6breaths/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 theProteus 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 eventsrelated to or possibly related to Proteus Personal Monitor System
Non-serious AEs--92% mild, 8%moderate
Adverse Event (AE) – IngestibleSensor		Rate as% ofsubjects	Rate as %ofingestions
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)cleared component)
Localized skin irritation andinflammation	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,inclusive of PPM-only users (IEMingestion)	99.3% Detection accuracy100% Correct identificationNo SAEs / UADEs related to system
11,655 ingestions
3810 subject-days of systemutilization
Maximum daily ingestion: 34 IEMs
Maximum system utilization: 42days

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 TestingLabeling (dose limits)
Systemic toxicity	Toxicology TestingLabeling (dose limits)
Electromagnetic incompatibility	Electromagnetic Compatibility TestingWireless testingLabeling
Electrical safety issues	Electrical Safety TestingLabeling
Electrical/Mechanical failure	Non-clinical Performance Testing
Failure to mark event	Non-clinical Performance TestingClinical Evaluation
Failure to excrete	Animal Testing
Usability	Human Factors TestingLabeling

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;
1. 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;
1. Appropriate analysis and non-clinical testing must validate electromagnetic compatibility (EMC) performance, wireless performance, and electrical safety; and
1. 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

Regulation Number and Section

§ 880.6305 Ingestible event marker.

(a)
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.(b)
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.