clinical evaluation report for resmed bilevel sleep devices

CLINICAL EVALUATION REPORT FOR RESMED BILEVEL SLEEP DEVICES

(Doc. #: D370-1459 Rev. 2.0)

Proprietary Information, not to be reproduced or made available to third parties without prior consent from ResMed and not to be used in any unauthorised way. ResMed Ltd 2019

Date last saved: 29-May-19 | Objective id: D370-1459 Bilevel Sleep Clinical Evaluation Report.docx | Page 1 of 135

Title: CLINICAL EVALUATION REPORT FOR RESMED BILEVEL SLEEP DEVICES

Products: AIRCURVE 10 S, AIRCURVE 10 ST AND AIRCURVE 10 VAUTO

Number: D370-1459

Revision: 2.0

Date of CER: 29/05/19

Date of next CER: Five years from publication date

Report prepared by: Sophia Karok, Medical Writer

“I have verified that the attached CER supports the clinical performance and safety of the above device/s. I do not have any conflicts of interest to declare.”

Competent clinical expert: Carlos Nunez, MD and Martin Devitt, BMED


(Doc. #: D370-1459 Rev. 2.0)

Company Confidential


1. EXECUTIVE SUMMARY 6

2. SCOPE OF THE CLINICAL EVALUATION 7

2.1 Devices under evaluation 8

2.1.1 Accessories 9

2.2 Directive / Regulation 11

2.3 Device description 11

2.3.1 Device specifications 12

2.3.2 System architecture 14

2.3.2.1 Power supply (1) 15

2.3.2.2 User interface (2) 15

2.3.2.3 Blower assembly and air path (3) 16

2.3.2.4 Microprocessor controller (4) 16

2.3.2.5 SD card and oximetry modules (5) 16

2.3.2.6 Humidifier (6) 17

2.3.2.7 Air tubing (7) 17

2.3.2.8 Wireless module (8) 17

2.3.3 Materials 18

2.4 Technology 19

2.4.1 Therapy modes 20

2.4.1.1 CPAP 21

2.4.1.2 Bilevel 21

2.4.1.2.1 Bilevel S mode 22

2.4.1.2.2 Bilevel S/T mode 23

2.4.1.2.3 Bilevel T Mode 23

2.4.1.3 VAuto 23

2.5 Device group 25

2.6 Intended purpose 25

2.6.1 Contraindications 26

2.7 Claims 26

2.7.1 AirCurve 10 S 26

2.7.2 AirCurve 10 ST 29

2.7.3 AirCurve 10 VAuto 31


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2.8 Regulatory history 34

2.9 Changes 35

3. OVERVIEW OF THE CLINICAL BACKGROUND AND THE “STATE OF THE ART” 36

3.1 Medical fields 36

3.2 Literature search strategy 36

3.3 Applicable standards and guidance documents 37

3.4 Description of medical conditions 39

3.5 Descriptions of available therapeutic options 40

3.6 Hazards 45

3.7 Types of users 52

3.8 Diverging opinions of professionals as to the use of the different medical options 54

3.9 Unmet medical needs 55

4. MEDICAL DEVICE/S UNDER EVALUATION 56

4.1 Type of evaluation 56

4.2 Demonstration of equivalence 56

4.3 Clinical data generated and held by the manufacturer 57

4.3.1 Premarket clinical investigations 57

4.3.2 Clinical data generated from risk management activities and PMS programmes 57

4.3.2.1 PMCF studies 57

4.3.2.2 PMS reports, including vigilance reports and trend reports 59

4.3.2.2.1 Trend reports 59

4.3.2.2.2 Vigilance reports 66

4.3.2.3 Literature search and evaluation reports for PMS 72

4.3.2.4 Complaints regarding performance and safety sent to the manufacturer, including the manufacturer’s own evaluation and report 73

4.3.2.4.1 Death - Device 76

4.3.2.4.2 Adverse events other than death - Device 77

4.3.2.4.3 Death - Accessories 79

4.3.2.4.4 Adverse events other than death - Accessories 79

4.3.2.5 Field Safety Corrective Actions 82

4.3.3 Preclinical studies 84


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4.3.3.1 Standards compliance reports 84

4.3.3.2 System verification reports 85

4.3.3.2.1 Pressure performance 85

4.3.3.2.2 Comfort Algorithm Parameters 85

4.3.3.2.3 FG Interfaces and Comms 86

4.3.3.2.4 Therapy Functionalities 86

4.3.3.2.5 Therapy Waveform Performance 87

4.3.3.2.6 Mechanical and Environmental Conditioning 87

4.3.3.2.7 Data Integrity 87

4.3.3.2.8 Visual Inspection 87

4.3.3.2.9 Safety and Mitigation 88

4.3.3.2.10 Power Supply 88

4.3.3.2.11 Humidification 88

4.3.3.3 Usability evaluation 88

4.3.3.4 Patient model bench testing 92

4.3.3.4.1 General Therapy Performance 92

4.3.3.4.2 Therapy Functions Verification 92

4.3.3.4.3 Therapy Validation 92

4.4 Clinical data from the literature 94

4.5 Appraisal of the clinical data 95

4.5.1 Clinical data generated and held by ResMed 96

4.5.1.1 Clinical investigations generated and held by ResMed 96

4.5.1.2 Clinical experience data 97

4.5.2 Clinical data from the literature 98

4.5.3 Conclusion of the appraisal of all clinical data 98

4.6 Analysis of the clinical data 101

4.6.1 Requirement on safety 101

4.6.2 Requirement on acceptable benefit-risk ratio 107

4.6.3 Requirement on performance 119

4.6.4 Requirement on acceptability of side-effects 122

5. CONCLUSION 125

6. IDENTIFICATION OF EVALUATORS 127

6.1 Conflict of Interest Statement/s of the Author/s 128

7. APPENDICES 129


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7.1 Appendix 1: References 129

7.1.1 Internal References 129

7.1.2 External References 130


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Rev Date Author/s Change Details Review

1.0 19/11/18 Sophia Karok

Original issue >D370-1459-1#1

2.0 29/05/19 Sophia Karok

Clarify that humidification is in scope of this clinical evaluation.

Electronic approval only

Items Definitions AirCurve 10 series

The devices under evaluation in this CER, namely, AirCurve 10 S, AirCurve 10 ST and AirCurve 10 VAuto.

AHI Apnoea / hypopnoea index APAP/AutoSet Automatically adjusting positive airway pressure CPAP Continuous positive airway pressure EPAP Expiratory positive airway pressure EPR Expiratory pressure relief IPAP Inspiratory positive airway pressure OSA Obstructive sleep apnoea PAP Positive airway pressure PG Polygraphy PSG Polysomnography

1. EXECUTIVE SUMMARY

The subject of this clinical evaluation report is the range of bilevel positive airway pressure (PAP) devices manufactured by ResMed, specifically the AirCurve 10 range of PAP devices indicated for obstructive sleep apnoea (OSA). Since this is the first clinical evaluation to the new requirements of the Medical Device Regulation (MDR) 2017/745, the purpose of this document is to analyse all historic information to support conformity of the present device range on the market.

The AirCurve 10 range is comprised of of three models. They are grouped as a device family based on the same intended use, clinical applications, hardware and modes of operation. The only difference between the three device models under evaluation is the range of activated therapy modes.

As per MDR Article 61 §10, ResMed has deemed that the demonstration of conformity with General Safety and Performance Requirements based on clinical data is not necessary. PAP therapy for OSA has a long history and is based on well-established technology and consistent claims with no significant innovative aspects. All PAP devices work by simple physiological mechanisms that involve generating low pressures of air delivered through a nasal or oronasal interface that keep the airway open during sleep. The device/body interaction is thus circumscribed to the resulting pneumatic splint along the pharyngeal airway caused by low air pressure.

Performance criteria and safety mitigations are clearly defined in harmonised standards, textbooks and guidance documents. The design of the AirCurve 10 device range has taken into account various internationally recognised standards including harmonised standards for basic safety and essential performance of sleep apnoea breathing therapy equipment. As such, ResMed is able to demonstrate compliance with the General Safety and Performance Requirements by meeting the requirements of these internationally recognised standards.


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The clinical evaluation identifies, appraises and analyses all relevant clinical data to validate the ongoing safety and performance of the devices on the market as per MDR Annex XIV §1. This includes any premarket clinical investigations, PMCF studies, postmarket reports and usability evaluations undertaken by ResMed.

The clinical evaluation of the AirCurve 10 device range also draws on all pertinent data from the literature on the devices under evaluation for their intended purpose as well as on PAP therapy in general with regards to safety, performance and clinical background.

These data, together with the results of the risk analysis, are deemed sufficient to support the General Safety and Performance Requirements of ResMed’s AirCurve 10 series.

No unacceptable risks were identified in the risk analysis for the AirCurve 10 devices that require clinical data in order to be addressed and there were no new potential risks identified during the evaluation of the preclinical and clinical data (including post-market) as part of this clinical evaluation. This clinical evaluation report establishes that the benefit-risk ratio for the AirCurve 10 device range is favourable and acceptable in line with the state of the art.

Therefore, the currently available preclinical and clinical data, together with the results of the risk analysis, support the ongoing performance and safety of the AirCurve 10 series of PAP devices for sleep apnoea.

2. SCOPE OF THE CLINICAL EVALUATION

The objective of the clinical evaluation is to support conformity of ResMed’s bilevel sleep PAP devices with the Medical Devices Regulation (MDR) 2017/745 General Safety and Performance Requirements, specifically sections 1, 2, 3, 4, 5, 6, 8, 10 and 23 of Annex I.

The basic function of PAP devices is to deliver air at therapeutic pressures that acts as a pneumatic splint to prevent the collapse of the pharyngeal airway in patients suffering from obstructive sleep apnoea (OSA). It was first demonstrated in a 1981 proof-of-principle study by Professor Colin Sullivan (1). The paper describes the successful treatment of five patients with OSA by maintaining a continuous pressure of air to the patient during sleep via a nasal mask.

ResMed’s AirCurve 10 range provides PAP in continuous (CPAP), variable (bilevel) and self-adjusting (VAuto) modes for OSA patients. The AirCurve 10 S and the AirCurve 10 ST are indicated for the treatment of OSA in patients weighing more than 13 kg and the AirCurve 10 VAuto is indicated for OSA patients weighing more than 30 kg and more than 13 kg in CPAP and S modes. They are all intended for home and hospital use.

ResMed’s AirCurve 10 range of bilevel PAP devices for OSA are positioned in the same way as other ventilators that deliver bilevel PAP via well-established technology. Performance criteria and safety mitigations are clearly defined in harmonised standards (ISO 80601-2-70:2015), which have been incorporated into the design of the AirCurve 10 range internal ref. 1. As such, ResMed is able to demonstrate compliance with the General Safety and Performance Requirements by meeting the requirements of these internationally recognised standards.

The clinical evaluation of the AirCurve 10 device range draws on all pertinent data from the literature on the devices for their intended purpose as well as on bilevel PAP therapy in general with regards to safety, performance and clinical background. In addition, clinical data relevant to device under evaluation derived from premarket clinical investigations, PMCF studies, postmarket reports and usability evaluations are identified, appraised and analysed as outlined in the clinical evaluation plan internal ref. 4.


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All AirCurve 10 bilevel PAP models are operating on the same therapy algorithms that have been safely and effectively used in ResMed bilevel PAP devices placed on the market for many years.

The evaluation and summation of all available clinical data, favourable or unfavourable, for the present device range including accessories are reported with regards to its intended use and marketing claims and appraised for conformity to MDR’s General Safety and Performance Requirements.

2.1 Devices under evaluation

The clinical evaluation covers the AirCurve 10 range of bilevel PAP devices for OSA manufactured by ResMed (ResMed Pty Limited, 1 Elizabeth Macarthur Drive, Bella Vista, NSW, 2153, Australia) and subcontract manufacture by ResMed Asia Operations Pty. Ltd. (8 Loyang Crescent, #05-01, 509016 Singapore). The AirCurve 10 series was developed under the Newport project and includes the following three models:

AirCurve 10 S AirCurve 10 ST AirCurve 10 VAuto

The AirCurve 10 devices are based on existing technology aligned to the same clinical applications as other bilevel PAP therapy devices currently on the market. Changes from previous to present device ranges are circumscribed to user interface, updated operating system, minor material change and wireless data transfer.

The devices under evaluation all share the same intended use, clinical applications, hardware and modes of operation. All systems comprise the flow generator, patient tubing, mask (patient interface) and humidifier. The only difference between the three models is circumscribed to therapy modes activated within the software and associated changes to the settings and screens on the user interface.

The treatment modes available across AirCurve 10 devices include:

CPAP mode (fixed-pressure): the device delivers a continuous positive airway pressure throughout the therapy session with and without expiratory pressure relief (EPR).

Bilevel mode (IPAP and EPAP): the flow generator augments any breath initiated by the patient by detecting the onset of inspiration or expiration and delivering the set Inspiratory Positive Airway Pressure (IPAP) and Expiratory Positive Airway Pressure (EPAP). Bilevel Mode is sub-divided into three further modes:

o Bilevel (S) Mode (spontaneous IPAP and EPAP) o Bilevel (S/T) Mode (spontaneous/timed IPAP and EPAP) o Bilevel (T) Mode (timed IPAP and EPAP)

VAuto mode (self-adjusting): the mean airway pressure (between IPAP and EPAP) will self-

adjust based upon breathing events.

Device Modes available

CPAP Bilevel (S) Bilevel (T) Bilevel (ST) VAuto

AirCurve 10 S Y Y N N N

AirCurve 10 ST Y Y Y Y N


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AirCurve 10 VAuto Y Y N N Y

Importantly, each therapy mode when implemented in different AirCurve 10 models operates on identical algorithms. Given the considerable overlap of identical therapy modes across different AirCurve 10 devices, it was deemed important to capture clinical data potentially pertinent to more than one device in the same clinical evaluation. How data sets relate to a specific device or therapy mode will be analysed individually.

2.1.1 Accessories

Air Curve 10 devices are flow generators that are used with a number of accessories and supporting products as tabulated below. Accessories that have a significant clinical benefit and operate autonomously compel a separate clinical evaluation. Other accessories may be considered as merely assisting the devices of concern. Where appropriate, performance standards are verified with compliance to harmonised standards. All accessories listed below are assessed together in this CER with some exceptions (see column “Remarks” for more information).

AirCurve 10 S/ST/VAuto

Device package:

Flow Generator Humidifier Tubing SD Card Travel Bag Power Supply Unit

ACCESSORIES DEVICE CLASSIFICATION REMARKS

Tubing

ClimateLine Air Accessory Therapy delivery from a PAP device always includes use of tubing,

therefore, all clinical evidence valid to PAP devices is also applicable to

tubing. Verification testing (internal ref. 27) is sufficient to confirm the devices maintain their intended performance

with the addition of oxygen (ClimateLine Air Oxy) and therefore

meet the intended use.

ClimateLine Air Oxy (with oxygen

connector port)

Accessory

SlimLine Accessory

Standard Accessory / Spare Part Tubing Wrap Accessory Tubing Wrap

SlimLine Accessory

HumidAir humidifier

Standard water tub

Accessory / Spare Part System verification testing (internal ref.

27) includes therapy delivery from a PAP device with humidification and is

thereby is sufficient to confirm the devices maintain their intended

performance with humidification.

Cleanable water tub

Accessory / Spare Part

Filter

Filter cover Spare Part Therapy delivery from a PAP device always includes use of an inlet filter,

therefore, all clinical evidence valid to PAP devices is also applicable to filters. Hypoallergenic filters mechanically filter bacteria with >99% efficiency (internal

ref. 17)

Hypoallergenic Filter

Accessory

Standard Filter Spare Part

Supporting products

DC-DC Converter

Accessory / Spare Part DC converters provide power only and do not fulfil a specific clinical function. Verification testing (internal ref. 27) is


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sufficient to confirm the devices maintain their intended performance

with the power supply units.

SD Card Reader Non-Medical Device

This is a third party product. SD cards enable device data to be reviewed but

have no direct impact on device effectiveness or safety.

Oximeter Module

Accessory

The oximeter module enables use of third-party oximetry accessories.

Oximetry data is not used directly by the PAP device and is for information

only. ResMed verifies compatibility, but clinical evaluation is the responsibility of

the third-party manufacturer. Serial Module Accessory Not a medical device.

USB Module Accessory

Not a medical device. USB modules enable device data to be extracted but

have no direct impact on device effectiveness or safety.

Power Station II Accessory

Batteries provide power only and do not fulfil a specific clinical function.

Verification testing (internal ref. 27) is sufficient to confirm the devices

maintain their intended performance with the power supply units.

Tubing Elbow Accessory

Therapy delivery from a PAP device always includes use of tubing, therefore

all clinical evidence valid to PAP devices is also applicable to tubing. The tubing elbow fulfils the same

functionality as other tubing. Travel bag and Travel bag For

Her Non-Medical Device

Not a medical device. The travel bag is an accessory of convenience and has no impact on the device performance.

Air10 Side Cover Charcoal

Spare Part

Not a medical device. This is a spare part of the outer chassis of the device

and has no impact on the device performance.

Air10 Air outlet Spare Part

Verification testing (internal ref. 27) is sufficient to confirm the devices meet

their intended performance with the use of an air outlet and therefore meet the

intended use.


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2.2 Directive / Regulation

This clinical evaluation is developed in accordance with:

Medical Device Regulation (MDR) 2017/745 on medical devices amending the Medical Device Directive (MDD) 93/42/EEC;

European guidance document (MEDDEV 2.7.1 Rev. 4 Clinical evaluation: A guide for manufacturers and Notified Bodies under Directives 93/42/EEC and 90/385/EEC4);

Therapeutic Goods (Medical Devices) Regulations 2002; TGA guidance document (Clinical Evidence Guidelines - Medical Devices - Version 1.0,

February 2017); and Applicable requirements of sections 10 to 20 of the Canadian Medical Devices Regulations

(SOR/98/282).

2.3 Device description

The basic function of PAP devices is to deliver air at therapeutic pressures, which acts as a pneumatic air splint to maintain patency of the upper airway in patients with OSA. CPAP is considered the treatment of choice for moderate-severe OSA (2).

The principle of CPAP was first demonstrated by Professor Colin Sullivan in a 1981 study published in Lancet (1). The paper describes the successful treatment of five patients with OSA by maintaining a continuous pressure of air via a nasal mask during sleep. Sullivan went on to patent the technology. In 1987, Dr Peter Farrell invested into Sullivan’s technology while working for Baxter International before founding ResCare (now ResMed) in 1989. ResMed was the first company to commercialise home CPAP devices and has been pioneering PAP therapy for 30 years.

Bilevel PAP therapy was originally conceived with the idea of varying the administered pressure between the inspiratory and expiratory cycles (IPAP and EPAP) (3-5). A variable pressure setting decreases the amount of pressure against which the patient exhales, thereby decreasing abdominal muscle recruitment and consequent respiratory discomfort during the expiratory cycle. Bilevel therapy is generally recommended for patients to increase comfort and compliance in noncompliant OSA patients (6, 7), for patients who need a higher pressure (8) and for patients who need ventilatory assistance

(9).

ResMed developed the VAuto therapy mode to address changes in the patient’s breathing pattern. VAuto delivers two pressures (IPAP and EPAP) that change throughout the night on a breath-by-breath basis, but the pressure support (difference between EPAP and IPAP) remains the same. VAuto may be suitable for patients who desire automatic titration of EPAP and do not require pressure support levels above 10 cm H2O.

Patient comfort features introduced to PAP therapy in recent years include new mask interfaces, expiratory pressure relief function, heated humidifiers and tubing. These are design features aimed to improve compliance and comfort.

The principles of PAP therapy remain unchanged since their discovery. ResMed’s range of bilevel PAP devices are based on well-established technology aligned to the same clinical applications and harmonised performance standards as used by other bilevel PAP devices with years of safe and effective use on the market.

The present device range does not incorporate medicinal substances, tissues, or blood products. They are non-sterile and do not emit radiation (with the exception of the non-harmful radio frequency emitted via cellular module).


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2.3.1 Device specifications

The table below summarises the specification of AirCurve 10 devices. The purpose of the table is to clarify differences and similarities between models of the device family covered in the clinical evaluation (please note this is not an equivalence table).

DIFFERENCES

AirCurve 10 S AirCurve 10 ST AirCurve 10 VAuto

Indications for use

The AirCurve 10 S device is indicated for the treatment of OSA in patients weighing more than 13 kg.

The AirCurve 10 ST device is indicated for the treatment of OSA in patients weighing more than 13 kg.

The AirCurve 10 VAuto device is indicated for the treatment of OSA in patients weighing more than 30 kg and more than 13 kg in CPAP and S modes.

Therapy modes CPAP Bilevel (S)

CPAP Bilevel (S) Bilevel (T) Bilevel (ST)

CPAP Bilevel (S) VAuto

NO DIFFERENCES

Visual

Location of use Hospital/home Pressure range 2-25 cm H2O Ramp settings Ramp time between 5 and 45 minutes Easy-Breathe waveform

Yes

Smart start/stop Yes Mask fit Yes Climate control Yes Enhanced Climate Control Auto

Yes

Trigger and cycle Yes VSync leak management

Yes

Telemonitoring AirView and myAir User interface LCD screen and controls Stored data viewing Flow generator LCD screen Data transfer medium SD Card and wireless Motor Brush-less low voltage DC Power supply 100-240V, 50-60Hz Fan type Multiple impeller axial motor Weight 1248 g Dimensions (H x W x D)

116 mm x 255 mm x 150 mm


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Supplemental oxygen Labelled for use with supplemental oxygen

Designed life Device, power supply unit: 5 years Air tubing and air filter: 6 months Cleanable humidifier: 2.5 years

Sound pressure and power level

25-27±2 dBA and 33-35± 2 dBA

Harmonised standards

ISO 80601-2-70:2015 ISO 14971:2007 IEC 60601-1:2005/A1:2012 IEC 60601-1-2:2014 IEC 60601-1-6:2010/A1:2013 IEC 60601-1-11:2015 ISO 10993-1:2009 IEC 62304:2006/A1:2015 ISO 80601-2-74:2017 ISO 15223-1:2016


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2.3.2 System architecture

All systems in the present device range comprise the flow generator, patient tubing and humidifier (see Figure 1 for an example). This set-up is used in combination with a vented mask system such as a nasal pillow, nasal or full face mask (outside the scope of this clinical evaluation).

Figure 1. AirCurve 10 ST flow generator with HumidAir integrated humidifier, ClimateLine tubing and AirFit F10 full face mask

The following block diagram shows the various electrical components in the AirCurve 10 platform (Figure 2). The subsequent sections describe each numbered component in more detail.

1 2

4

3

5

6

7

8

Figure 2. Schematic top-level electrical diagram of an AirCurve 10 device.


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2.3.2.1 Power supply (1)

The 90 Watt power supply unit in AirCurve 10 devices contains a standard Switch Mode Power Supply (SMPS) universal input (100/240V AC, 50/60 Hz). The power supply units meet IEC 60601-1 (International Standard), and IEC 60950 (Power supplies used in Information Technology devices).

Summary of plug pack specifications:

INPUT

Nominal input 100-240VAC Frequency 50-60Hz Isolation Class II Double isolation, type BF

OUTPUT

Voltage 24VDC nominally

2.3.2.2 User interface (2)

The control panel consists of simple buttons and a dial to navigate the user interface (Figure 3).

Figure 3. Control panel in AirCurve 10 devices

The user interface of the AirCurve 10 series is represented below (Figure 4). It comprises various indicators and controls, including a colour LCD display that displays clinical data and allows the user to view device performance and patient information and to set and adjust flow generator parameters. An LCD screen backlight provides indication that the device is on and facilitates easy access to the device in low light environments.

Figure 4. AirCurve 10 user interface showing the (a) patient menu and unlocked (b) clinical menu


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The patient menu (Figure 4a) has two choices: My Options, where patients can change their comfort settings including Ramp and Climate Control, and Sleep Report, to give patients the basic information about their sleep therapy (usage hours, events per hour, mask seal and humidifer function).

The clinical menu (Figure 4b) is unlocked by the clinician using a specific key combination. The clinical menu has two choices: Settings, where the therapy parameters are specified (mode, IPAP, EPAP, Easy-Breathe etc.), and Sleep Report, which displays more detailed usage data (including days used, usage hours, pressue, leak, AHI, AI).

2.3.2.3 Blower assembly and air path (3)

In AirCurve 10 devices, the blower generates and controls positive air pressure to be delivered to the patient. Its components include a brushless DC motor, impeller and housing. The air path inside the flow generator contacts air supplied to the patient’s airways via an air filter at the inlet to the flow generator, the blower assembly enclosure (including impeller), the tubing as well as internal pressure and flow sensors. The flow sensor can detect the flow rate, and the pressure sensor detects the pressure. Flow and pressure sensors provide patient and machine data to the microprocessor controller.

2.3.2.4 Microprocessor controller (4)

The microprocessor controller in each AirCurve 10 device receives data from the pressure and flow sensors in the same manner. This information is then used to determine the new pressure set point and a command is sent to the motor controller to adjust the motor speed to maintain the required mask pressure.

The microprocessor controller is designed to provide the following functions: Provision of therapeutic pressure Flow and pressure sensor integrity monitoring Signal processing Control of the user interface Access to program and data memory

2.3.2.5 SD card and oximetry modules (5)

AirCurve 10 devices use a connection port for Secure Data (SD) card allowing the transfer of patient and machine information to a PC where the data can be viewed by a PC based application such as ResScan.

Pulse oximetry is supplied as an optional extra for AirCurve 10 devices. The Nonin pulse oximeter is intended to record patient oxygen saturation and pulse rate data. The principle of pulse oximetry is based on the red and infrared light absorption characteristics of oxygenated and deoxygenated haemoglobin. The Nonin Pulse is currently CE marked and is sold separately. Nonin supplies the pulse oximeter to ResMed and other manufacturers as a medical device accessory. The ResMed Oximetery Module creates an interface between the AirCurve 10 platform, the Nonin oximeter (Xpod Model 3012) and the Flex probe (8000J) secured to the patient’s finger by the Flex wrap.


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2.3.2.6 Humidifier (6)

All AirCurve 10 devices feature humidification to facilitate heat and moisture retainment in the airway circuit in order to alleviate dryness of patients’ upper airways. The humidifier is fully integrated in the AirCurve 10 series with a removable tub. The tub can be removed and replaced with an end cap for a configuration without humidification.

The integrated heated HumidAir humidifier directs the airflow from the flow generator to the patient’s breathing circuit via the water chamber. The chamber consists of an enclosed reservoir partly filled with water that is heated via a thermostatically controlled heating plate, the temperature of which is set manually by the patient or clinician. Air from the flow generator enters the enclosure via the inlet and leaves via the outlet. As the air passes over the warmed water within the chamber, it is moistened. The water chamber is fully detachable and can be disassembled, cleaned and re-assembled. A thermal sensor is designed to ensure correct water temperature is maintained based upon the desired setting. The inclusion of the heated tubing enables better control of potential rain-out and better humidification stability over a wide range of environmental conditions.

The Climate Control algorithm controls the HumidAir humidifier and ClimateLineAir heated air tubing to deliver constant humidity and temperature outputs. The system adjusts automatically to changes in ambient room temperature and humidity values, flow due to pressure changes and flow due to mask or mouth leak. Automatic climate control sets the tube temperature at 27°C and relative humidity at 85%. With manual climate control, the tube temperature can be set to anywhere between 16–30°C and humidity levels between 1 and 8 (where 1 is the lowest humidity setting and 8 is the highest humidity setting). Rainout protection is not guaranteed in manual climate control.

2.3.2.7 Air tubing (7)

The standard air tubing for AirCurve 10 devices are 2m (6ft 6in) in length with a small diameter air tube (15 mm). The material is designed to be ultra-light and flexible.

The ClimateLineAir heated air tube is available separately and provides additional humidity control by monitoring temperature levels allowing the device to compensate as ambient conditions change (Climate Control function).

2.3.2.8 Wireless module (8)

The internal wireless is a CDMA Cellular Network (North American AirCurve 10 ST) or GSM (ROW AirCurve 10 ST) module and can operate on both 800 – MHz and 1.9 – GHz. The wireless module is internal to the AirCurve 10 platform.

The wireless function in AirCurve 10 devices does not have any direct effect on the delivery of therapy to the patient, it is only used for reporting data and changing settings values. The primary functions of wireless technology in the AirCurve 10 are to upload therapy data and flow generator status information (settings values, error events etc.) to a cloud database for later access by clinicians and other users and download settings changes to the AirCurve 10 device. The purpose of using wireless technology is to allow these functions to be performed remotely.

All messages between a device and a ResMed cloud database are authenticated by the use of a secret key and MD5 hash codes. In addition, no patient identified data is transmitted in any of the messages. The data is identified only by the serial number of the device it has come from or is destined for.


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2.3.3 Materials

The materials used and patient contacting components in AirCurve 10 devices may be configured as:

a flow generator only, where the air-path is dry, or with optional humidification of the delivered air, where the air-path downstream of the water

tub is warm/moist.

All materials in the devices under evaluation have been assessed for biocompatibility in accordance with ISO 10993: Biological evaluation of medical devices and ISO 18562-1: Biocompatibility evaluation of breathing gas pathways in healthcare applications -- Part 1: Evaluation and testing within a risk management process. All Biocompatibility testing for has been performed using cytotoxicity, sensitisation and extractables and leachables for materials located in the respiratory pathway and cover REACH, RoHS and Health Canada (BPA and DEHP Requirements) internal ref. 18, 19 and 20. The conformity with Nanomaterials requirements will be claimed by Nanomaterials position statement. An analysis of hazardous materials is provided in 4.6.2.

A summary of all patient contacting components and their respective materials are summarised in the table below:

Patient contacting component

Material type Exposure type

Air filter

Standard: Polyester thermally bonded fibres Hypoallergenic: Polypropylene, polyester & acrylic fibres

Indirect dry air-path; occasional skin contact

Filter Cover PC/ABS (Polycarbonate/Acrylonitrile Butadiene Styrene)

Indirect dry air-path; occasional skin contact

Side Panel PC/ABS Indirect dry air-path; occasional skin contact

Air tubing Thermoplastic elastomers (TPE); polypropylene; ethylene octene copolymer; polypropylene

Indirect dry air-path

Venturi PB (seal) TPE (thermoplastic vulcanizates) Indirect dry air-path

PB Muffler PB Inlet

30% Glass-filled polypropylene Indirect dry air-path

PB Flow Plate ABS Indirect dry air-path

Motor/Blower assembly Various materials including thermoplastic polyester


Flow Restrictor Polypropylene Indirect dry air-path

Pressure Sensor Various materials (manufacturer: GE Sensing)


Flow Sensor Various materials (manufacturer: Sensirion)


Suspension Seal Silicone Indirect dry air-path Foams – acoustic various Polyurethane Indirect dry air-path Flow Sensor Seal TPE (thermoplastic vulcanizates) Indirect dry air-path

Chassis Inlet Seal (with over-mould)

Glass-filled polybutylene terephthalate; silicone (over-mould)


FG End Cap Assembly Silicone; glass-filled polypropylene Indirect dry air-path;


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occasional skin contact

MPMU Outlet (seal) Glass-filled polybutylene terephthalate; silicone (over-mould)

Wet air-path; occasional skin contact

Humidifier Tub Plate (base) Stainless Steel grade 304 Wet air-path

Tub Plate over moulded seal Aluminium Wet air-path

Tub Lid Seal Assembly Nylon; silicone (over-mould) Wet air-path

Tub Lid and Tub Lower ABS Wet air-path; occasional skin contact

2.4 Technology

PAP therapy for OSA is based on well-established technology. The AirCurve 10 range of bilevel PAP devices for OSA is aligned to the same clinical applications and harmonised performance standards as used by hundreds of PAP devices with years of safe and effective use on the market.

AirCurve 10 devices treat OSA by simple modes of action. By delivering air at therapeutic pressures, a positive pharyngeal transmural pressure is maintained so that the internal pressure exceeds the surrounding pressure (10). PAP also stabilizes the upper airway through increased end-expiratory lung volume (10). As a result, respiratory events due to upper airway collapse, such as apnoeas and hypopnoeas, are prevented.

The principle of operation of AirCurve 10 devices is a micro-processor controlled blower system that generates positive airway pressure from 3-25 cm H2O, as required, to maintain an air splint for effective treatment of OSA (some variants in Germany are 2-25 cm H2O). Each therapy mode when implemented in a different AirCurve 10 model operates on identical algorithms.

CPAP for OSA treatment involves the application of continuous positive airway pressure to the patient at a fixed level sufficient to keep the patient’s airway open. Patients who do not tolerate CPAP may find bilevel S mode more comfortable. Bilevel PAP assists spontaneous breathing by cycling between two pressures in response to the patient flow or a pre-set fixed time. The IPAP assists inspiration while the lower EPAP facilitates exhalation while providing a splint to maintain an open upper airway.

In S mode, two treatment pressures may be set – one for inspiration (IPAP) and one for expiration (EPAP). The device senses when the patient is inhaling and exhaling and supplies the pressures accordingly. The delta between IPAP and EPAP can be set to a maximum of 22 cm H2O. In bilevel S/T mode, the device will also supply additional breaths should the patient breath rate fall below set backup breath rate. In bilevel T mode, the fixed breath rate and the fixed inspiration/expiration time set by the clinician is supplied regardless of patient effort. VAuto is a variant of bilevel S where the mean airway pressure will alter based upon breathing events. See section 2.4.1 for more detail on therapy modes.

The design of the AirCurve 10 range has taken into account numerous internationally recognised standards for basic safety and essential performance of sleep apnoea breathing therapy equipment (ISO 80601-2-70:2015). Such harmonised standards identify design requirements for sleep apnoea breathing therapy equipment, such as, for example, requiring that delivery of dynamic and static airway pressures is accurate and stable in each therapy mode and securing protection against hazards from the device and its components. Tests were conducted on static and dynamic airway pressure accuracy, maximum flow, acoustic energy, overpressure, and CO2 rebreathing and compliance with ISO 80601-2-70 was confirmed internal ref. 1. More detail in section 4.3.3.1.


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The modes and performance parameters for PAP therapy are well-established and published in key textbooks, such as:

Buchanan P, Grunstein RR. 2011. Positive airway pressure treatment for obstructive sleep apnea-hypopnea syndrome. In: Kryger MH, Roth T, Dement WC. (Eds.). Principles and Practice of Sleep Medicine (5th Ed), Philadelphia: Saunders/Elsevier, pp. 1233-1249.

Berry RB. 2010. Positive Airway Pressure Therapy, An Issue of Sleep Medicine Clinics, Philadelphia: Saunders/Elsevier.

Kushida CA. 2007. Obstructive Sleep Apnea, Bosa Rosa: Taylor & Francis Inc. Kuźniar TJ. 2016. New approaches to positive airway pressure treatment in obstructive sleep

apnea. In: Freedman N (Ed.). Novel Approaches to the Management of Sleep-Disordered Breathing, An Issue of Sleep Medicine Clinics, Philadelphia: Saunders/Elsevier, pp. 153-159.

All devices in the clinical evaluation feature humidification systems. Humidification with PAP reduces the risk of side effects and provides a means to improve the compliance and comfort of the delivered therapy with some success (11, 12). AirCurve 10 devices come with a fully integrated humidifier with detachable water tub. However, the bilevel PAP devices can also be used without humidification.

2.4.1 Therapy modes

The therapy modes available across AirCurve 10 devices include:

CPAP mode (fixed-pressure) Bilevel mode:

o Bilevel S Mode (spontaneous IPAP and EPAP) o Bilevel S/T Mode (spontaneous/timed IPAP and EPAP) o Bilevel T Mode (timed IPAP and EPAP)

VAuto mode (self-adjusting)

Device Modes available

CPAP Bilevel (S) Bilevel (T) Bilevel (ST) VAuto

AirCurve 10 S Y Y N N N

AirCurve 10 ST Y Y Y Y N

AirCurve 10 VAuto Y Y N N Y

The waveforms for the therapy modes are shown in Figure 5 below.


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Figure 5. CPAP, bilevel and VAuto waveforms

2.4.1.1 CPAP

CPAP mode involves the application of PAP at a fixed-pressure sufficient to keep the patient’s airway open. Patients who find the continuous application of CPAP uncomfortable may use the Expiratory Pressure Relief (EPR) comfort feature. This comfort feature reduces the pressure against which the patient exhales by -1 cm H2O, -2 cm H2O or -3 cm H2O. This is a patient preference, which does not alter their CPAP treatment regime.

Functions used in fixed-pressure CPAP mode:

Pressure Performance (IPAP and EPAP- locked together)

Breath– Detect, Record & Respond (Maintain CPAP)

Hypopnoea– Detect and Record

Apnoea– Detect and Record

Functions used in fixed-pressure CPAP mode with EPR:

Pressure Performance (IPAP and EPAP- locked together, pressure reduction on expiration)

Breath– Detect, Record & Respond (Maintain CPAP)


Apnoea– Detect, Record & Respond

2.4.1.2 Bilevel

Bilevel therapy is subdivided into three further main modes:

Bilevel S mode (spontaneous IPAP and EPAP) o Bilevel S mode with Easy-Breathe (spontaneous IPAP and EPAP with Easy-Breathe)

Bilevel S/T mode (spontaneous/timed IPAP and EPAP) Bilevel T mode (timed IPAP and EPAP)


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Functions used in bilevel mode:

Pressure Performance (IPAP and EPAP– clinician settable to provide pressure support)

Respiratory Rate (S/T & T modes)

Breath– Detect, Record & Respond (Maintain IPAP and EPAP)


Apnoea– Detect and Record

2.4.1.2.1 Bilevel S mode

In Spontaneous mode, two treatment pressures may be set -–one for inspiration (IPAP) and one for expiration (EPAP). The device senses when the patient is inhaling and exhaling and supplies the pressures accordingly. The difference between IPAP and EPAP levels helps determine the tidal volume. The delta between IPAP and EPAP can be set to a maximum of 22 cm H2O. The pressure range in bilevel S mode is 3-25 cm H2O (some variants in Germany are 2-25 cm H2O).

Bilevel S is the spontaneous mode of bilevel therapy, which means that the transition between IPAP and EPAP pressure is triggered by the patient’s respiratory cycle. The flow generator augments any breath initiated by the patient by detecting the onset of inspiration or expiration and delivering the set IPAP and EPAP pressures. To achieve synchronization between the delivered pressure and the patient’s breathing, the software monitors the airflow to and from the patient as illustrated in Figure 6. When the patient’s flow exceeds a pre-determined (trigger) value, the transition from EPAP to IPAP is initiated, this is called triggering. The clinician may set a time interval for the transition from EPAP to IPAP to occur, termed the rise time.

Figure 6. Synchronising IPAP and EPAP with patient’s respiratory cycle

At the end of a patient’s inspiration the patient flow drops which causes the software to change the pressure to the EPAP value, this is termed cycling. To ensure that synchronization is maintained in the presence of mouth leaks, the software provides for the setting of a time window for the inspiratory period. The clinician may set values for the minimum (Ti Min) and maximum (Ti Max) time that IPAP is maintained before cycling back to EPAP. This is illustrated in Figure 7.


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Bilevel S mode with Easy-Breathe provides improved comfort for patients who do not require fast pressure rise time. The Easy-Breathe pressure waveform provides gentle increases and decreases in pressure and replicates a more natural breathing experience.

Figure 7. Use of Ti Min and Ti Max for cycling

2.4.1.2.2 Bilevel S/T mode

Bilevel S/T is a variant of the bilevel S with the same patient-triggered respiratory cycle and the same inspiratory time window feature (Ti Min & Ti Max). In S/T mode, the clinician also specifies a respiratory rate that the patient shall not fall below (“backup rate”). This backup rate will be supplied if the patient’s spontaneous breathing rate is too low. In the event that the patient fails to spontaneously trigger a breath within the prescribed backup rate, a mandatory breath is initiated. The pressure range that can be delivered in bilevel S/T mode is 3-25 cm H2O (some variants in Germany are 2-25 cm H2O).

2.4.1.2.3 Bilevel T Mode

Bilevel T mode is a timed mode where the clinician specifies the respiratory rate and the length of the inspiratory portion of the breath (IPAP time). The breath state (inspiratory or expiratory) is predetermined by the IPAP time parameter and the backup rate setting. An inspiration is triggered each time after the Ti total, which is calculated from the set respiratory rate, has elapsed. An inspiration is cycled each time after the predetermined IPAP time has elapsed. The pressure range that can be delivered in bilevel T mode is 3-25 cm H2O (some variants in Germany are 2-25 cm H2O).

2.4.1.3 VAuto

VAuto mode is a variant on the bilevel S mode with Easy-Breathe, where the mean airway pressure (between IPAP and EPAP) is adjusted based on breathing events. The device self-adjusts the delivered mean airway pressure according to the state of the patient’s airway by responding to snoring, flow limitation and apnoea events. The difference between IPAP and EPAP values (“Pressure Support”) can be set by the clinician to varying levels up to a maximum of 10cm H2O. The pressure range that can be delivered in VAuto mode is 4-25 cm H2O.

Functions used in VAuto mode:


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Pressure Performance (AutoSet Pressure)- with clinician settable IPAP and EPAP to provide pressure support)

Breath– Detect, Record & Respond (Maintain Pressure Support and AutoSet Pressures)


Apnoea– Detect, Record & Respond

Flattening– Detect, Record & Respond

Snore– Detect, Record & Respond


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2.5 Device group

AirCurve 10 devices are bilevel PAP systems that fall within the GMDN 60712 (home BPAP unit). The devices use a micro-processor controlled blower system that generates positive airway pressure from 3-25 cm H2O during spontaneous respiration (some variants in Germany are 2-25 cm H2O). The device/body interaction is circumscribed to the resulting pneumatic splint along the pharyngeal airway caused by low atmospheric air pressure.

The basic function of PAP devices is to deliver air to the patient at therapeutic pressures applied through a nasal, oral or oral/nasal interface during sleep. The pressure prevents the repetitive collapse of the upper airway during sleep, characteristic of OSA. For patient groups treated with a PAP device the therapy is not life supporting. It is considered a low risk to the patient for the device to stop at any time during therapy, or to deliver air at a higher or lower pressure than prescribed. The AirCurve 10 device range has no Essential Performance (see 3.6).

PAP therapy is the treatment of choice for moderate-severe OSA (2). Patients who do not tolerate CPAP may find bilevel PAP more comfortable. Patients with mild OSA have additional treatment options. Behavioural measures, such as weight loss in overweight and obese patients and positional therapy are interventions with low-to-moderate degree evidence. There is currently insufficient evidence to support pharmacologic therapy for OSA (13).

Another measure for OSA is the use of oral appliances, such as mandibular repositioning devices (MRDs), worn while the patient is sleeping. Guideline and consensus documents have incorporated MRDs as a treatment option in patients with mild-to-moderate OSA, who do not respond to PAP or behavioural strategies (2).

Corrective upper airway surgery is an alternative for patients who do not respond to or tolerate less invasive treatment measures. There is currently no evidence to suggest superior effectiveness of surgical interventions over non-surgical interventions for OSA. Section 3.5 discusses available treatment options for OSA in more detail.

The AirCurve 10 device range is positioned in the same way as other PAP devices on the market that deliver CPAP, bilevel or self-adjusting PAP. Other manufacturers of PAP devices that feature the same indications for use and principles of therapy include Weinmann, Phillips Respironics, Puritan-Bennett, Fisher & Paykel, Breas, DeVilbiss and Transcend. The technical specifications across modern PAP devices are very similar with the most important one being pressure range and response to breathing events.

2.6 Intended purpose

As stated in their respective user guides internal ref. 2-3, the AirCurve 10 S and the AirCurve 10 ST are indicated for the treatment of OSA in patients weighing more than 13 kg and the AirCurve 10 VAuto is indicated for OSA patients weighing more than 30 kg and more than 13 kg in CPAP and S modes. They are all intended for home and hospital use. The person receiving therapy may operate the device themselves.

PAP is supplied continuously at a fixed level (CPAP) or at varying (bilevel) and self-adjusting (VAuto) pressure levels based upon measured respiratory parameters from the patient. The systems are designed for continuous operation. However, PAP devices are designed to be used whenever a person is asleep whether daytime or night time. Treatment adherence is a prerequisite in order for PAP devices to be effective. Patients are therefore required to continue therapy during OSA.


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PAP therapy may be used in OSA of any severity, but is most commonly prescribed for moderate-severe OSA (2) (see 3.5 for more detail). The stated clinical benefits of the devices under evaluation are in line with the general benefits associated with PAP therapy, such as reduced OSA severity and improved daytime sleepiness, oxygen saturation and quality of life (14) (see 2.7 for device-specific claims).

The variable pressure setting during bilevel PAP decreases the amount of pressure against which the patient exhales, thereby decreasing abdominal muscle recruitment and consequent respiratory discomfort during the expiratory cycle. Bilevel therapy is generally recommended for patients to increase comfort and compliance in noncompliant OSA patients (6, 7), for patients who need a higher pressure (8) and for patients who need respiratory assistance (9). With an overall lower average PAP delivered, difficulties caused by constant higher pressure such as discomfort, mask leak, mouth leak and bloating are reduced. Bilevel PAP thus helps extend the use of PAP to a wider patient group.

Humidification with PAP can also help reduce the risk of side effects and may provide a means to improve the compliance and comfort of the delivered therapy (11). All models from the AirCurve 10 range feature humidification systems with a fully integrated humidifier with detachable water tub. The humidifier is intended for single patient use in the home environment and re-use in a hospital/institutional environment.

2.6.1 Contraindications

As stated in their respective user guides internal ref. 2-3, the contraindications to PAP therapy listed by ResMed include:

– Severe bullous lung disease – Pneumothorax – Pathologically low blood pressure – Dehydration – Cerebrospinal fluid leak, recent cranial surgery or trauma

2.7 Claims

As discussed in the Risk-Benefit Analysis internal ref. 25, the clinical benefit statement of bilevel PAP devices for OSA is as follows:

The clinical benefit of CPAP and bilevel therapy for OSA is a reduction in apnoeas, hypopnoeas, sleepiness and improved quality of life.

The tables below summarise high-level claims for the AirSense 10 S, AirCurve 10 ST and AirCurve 10 VAuto separately with appropriate supporting evidence as indicated by the references.

2.7.1 AirCurve 10 S

Claim Supporting evidence

Claim source: Website


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THE AIRCURVE™ 10 S IS IDEAL FOR SLEEP APNOEA PATIENTS WHO FIND IT DIFFICULT TO ADJUST TO SLEEP APNOEA THERAPY ON A CONTINUOUS FIXED POSITIVE AIRWAY PRESSURE DEVICE, AS WELL AS PATIENTS WHO NEED EXTRA PRESSURE SUPPORT. THIS BILEVEL MACHINE HAS TWO DIFFERENT, ADJUSTABLE SET PRESSURES WHICH CAN MAKE THERAPY FEEL MORE COMFORTABLE.

--Purpose defined in Market Requirements Document (internal ref. 9) and tested in the system specifications (internal ref. 8).

--Bilevel therapy is generally recommended for adult and paediatric OSA patients if CPAP is not effective or if the patient is uncomfortable or intolerant of high CPAP (2, 8, 15,

16).

--See 2.4.1.1 and 2.4.1.2.1 for a description of the technology of CPAP and Bilevel S therapy modes featured in the AirCurve 10 S.

THE USER-FRIENDLY CONTROLS, INTUITIVE INTERFACE AND COLOUR LCD SCREEN MAKE IT SIMPLE TO NAVIGATE MENUS AND CUSTOMISE COMFORT SETTINGS

--Tested in various user interface evaluations (internal ref. 32, 35, 41, 42 and 44)

--See 2.3.2.2 for a description of the user interface featured in AirCurve 10 devices.

CONTINUOUS LEAK MANAGEMENT ENABLES RELIABLE DELIVERY OF THERAPY PRESSURE WHILE MAINTAINING PATIENT-DEVICE SYNCHRONY.

--Leak behaviour defined in the Clinical Requirements Document (internal ref. 10) and defined and tested in the system specifications (internal ref. 8).

THE AIRCURVE 10 S BILEVEL MACHINE IS COMPATIBLE WITH UP TO 15L/MIN OF SUPPLEMENTARY OXYGEN.

--Oxygen level defined in the Clinical Requirements Document (internal ref. 10) and defined and tested in the system specifications (internal ref. 8).

THE QUIET EASY-BREATHE MOTOR MAKES FOR A PEACEFUL ENVIRONMENT FOR YOU AND YOUR BED PARTNER.

--Noise levels defined tested in the system specifications (internal ref. 8).

Claim source: User Guide internal ref. 3 WHEN LEAK ALERT IS ENABLED, THE DEVICE BEEPS IF THE MASK LEAKS TOO MUCH AIR OR IF YOU REMOVE THE MASK DURING THERAPY.


WHEN SMARTSTART IS ENABLED, THERAPY STARTS AUTOMATICALLY WHEN YOU BREATHE INTO YOUR MASK. WHEN YOU REMOVE YOUR MASK, IT STOPS AUTOMATICALLY AFTER FEW SECONDS.

--Smart Smart is defined and tested in the system specifications (internal ref. 8).

--Refer to section 4.3.3.4.2 (Therapy Functions Verification).

Claim source: Brochure 1018392r2 internal ref. 5 FEATURING A SEAMLESSLY INTEGRATED CONNECTED CARE SYSTEM, THE AIRCURVE 10 S IS DESIGNED TO HELP YOU TREAT YOUR CHALLENGING OSA PATIENTS.

--AirView software behaviour is defined in the system software specifications (internal ref. 11).

--Telemonitoring and patient engagement tools have been shown to significantly improve treatment adherence when compared to standard care (17, 18).

WITH A NEW STYLISH DESIGN AND EVEN MORE SIMPLICITY, THE NEW AIRCURVE 10 S PROVIDES FIXED BILEVEL PRESSURE SUPPORT TO THOSE WHO NEED MORE RESPIRATORY COMFORT.


--User interface behaviour defined in the Clinical Requirements Document (internal ref. 10) and tested in the system specifications (internal ref. 8).


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RESMED’S AIRCURVE 10 S UTILISES A CONVENTIONAL SQUARE PRESSURE WAVEFORM DELIVERING TWO LEVELS OF PRESSURE – IPAP FOR INSPIRATION AND EPAP FOR EXPIRATION. THANKS TO ADVANCED SETTING CAPABILITIES (VSYNC, TICONTROL, AND TRIGGER & CYCLE SENSITIVITY), PRESSURE DELIVERY CAN BE FINE-TUNED FOR OPTIMISED BREATHING COMFORT

--Pressure waveform behaviour defined in the Clinical Requirements Document (internal ref. 10) and tested in the system specifications (internal ref. 8).


THE VSYNC ALGORITHM AUTOMATICALLY TRACKS AND COMPENSATES FOR LEAKS, FOR OPTIMAL DEVICE RESPONSE TO EVERY BREATH


TICONTROL™ (INSPIRATORY TIME CONTROL) ENABLES CUSTOMISATION TO THE PATIENT’S RESPIRATORY CONDITION AND A NORMAL BREATHING RHYTHM EVEN IN THE PRESENCE OF HIGH LEAKS.

--Pressure waveform behaviour defined in the Clinical Requirements Document (internal ref. 10) and defined and tested in the system specifications (internal ref. 8).

5 LEVELS OF TRIGGER & CYCLE SENSITIVITIES ALLOW FOR FINE-TUNED SYNCHRONISATION BREATH BY BREATH.


THE NEW HUMIDAIR™ HUMIDIFIER WITH CLIMATE CONTROL TECHNOLOGY ENSURES A CONSISTENT HUMIDIFICATION THROUGHOUT THE NIGHT.

--Clinical trial tested optimal temperature and humidity (internal ref. 12).

--Clinical trial tested HumidAir humidification system (internal ref. 13).

--Humidification testing to show consistent temperate done in humidifier system specifications (internal ref. 14).

--See 2.3.2.6 for a description of the humidification technology featured in the AirCurve 10 S.

THANKS TO AIRCURVE’S BUILT-IN WIRELESS TECHNOLOGY, AIRVIEW™ OFFERS IMMEDIATE INFORMATION ABOUT YOUR MOST CHALLENGING PATIENTS INCLUDING USAGE HOURS AND NIGHT PROFILE DATA.



REMOTE ASSIST ENABLES UNPRECEDENTED WIRELESS ACCESS TO DEVICE SETTINGS, HELPING YOU TO TROUBLESHOOT ANY TECHNICAL ISSUES REMOTELY IN MINUTES.


THERAPY SUMMARY DATA (365 DAYS) CAN BE VIEWED ON ANY DEVICE, RESSCAN™ SOFTWARE OR WIRELESSLY THROUGH AIRVIEW. ADDITIONAL 30 DAYS OF NIGHT PROFILE DATA ARE ALSO AVAILABLE REMOTELY ON AIRVIEW.

--ResScan software behaviour is defined in the system software specifications (internal ref. 15).



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2.7.2 AirCurve 10 ST


Claim source: Website THE AIRCURVE 10 ST IS A BILEVEL DEVICE WITH BACKUP RATE THAT PROVIDES EXCEPTIONAL PATIENT–VENTILATOR SYNCHRONY, REDUCING THE WORK OF BREATHING SO PATIENTS REMAIN COMFORTABLE AND WELL-VENTILATED. IT’S AN IDEAL CHOICE FOR RELIABLE, COST-EFFECTIVE NONINVASIVE VENTILATION WHEN ALARMS ARE NOT REQUIRED.

--Back-up rate behaviour defined in the Clinical Requirements Document (internal ref. 10) and defined and tested in the system specifications (internal ref. 8).

--Bilevel therapy is recommended for adult and paediatric OSA patients if CPAP is not effective or if the patient is uncomfortable or intolerant of high CPAP (2, 8, 15, 16). Typically, a transition from CPAP to bilevel PAP is encouraged when the pressure requirement approaches 15 cm H2O (15, 19, 20).

WITH THE AIRCURVE 10 ST CLIMATE CONTROL SYSTEM, YOU RECEIVE CONSTANT, COMFORTABLE TEMPERATURE AND HUMIDITY LEVELS DURING THERAPY. IT’S COMPRISED OF THE HUMIDAIR™ HUMIDIFIER, WHICH IS BUILT INTO THE MACHINE, AND THE CLIMATELINEAIR™ HEATED AIR TUBE.




--See 2.3.2.6 for a description of the humidification technology featured in the AirCurve 10 ST.

AVAILABLE TO ALL AIRCURVE 10 USERS, MYAIR IS AN EASY-TO-USE WEB PROGRAM THAT SYNCS UP WITH YOUR MACHINE TO LET YOU KNOW HOW YOU SLEPT THE NIGHT BEFORE, AND HELPS YOU STAY ON TRACK THROUGHOUT YOUR SLEEP APNEA TREATMENT JOURNEY.



CONTINUOUS LEAK MANAGEMENT ENABLES RELIABLE DELIVERY OF THERAPY PRESSURE WHILE MAINTAINING PATIENT-VENTILATOR SYNCHRONY.


ENHANCED DESIGN FEATURES LIKE AN UPRIGHT DESIGN THAT TAKES UP LESS OF YOUR BEDSIDE TABLE AND COLOR LCD SCREEN WITH INTUITIVE MENUS MAKE THE AIRCURVE 10 SERIES SIMPLE TO USE.




THE QUIET ENHANCED EASY-BREATHE MOTOR MAKES FOR A PEACEFUL ENVIRONMENT FOR YOU AND YOUR BED PARTNER.

--Noise levels defined and tested in the system specifications (internal ref. 8).

--See 2.4.1.2.1 for a description of the Easy-Breathe waveform.


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Claim source: Brochure 1018393r2 internal ref. 6 FEATURING A SEAMLESSLY INTEGRATED CONNECTED CARE SYSTEM, THE AIRCURVE 10 ST IS DESIGNED TO HELP YOU TREAT YOUR CHALLENGING OSA PATIENTS.



WITH A NEW STYLISH DESIGN AND EVEN MORE SIMPLICITY, THE NEW AIRCURVE 10 ST PROVIDES FIXED PRESSURE SUPPORT AND ADJUSTABLE BACK UP RATE TO THOSE WHO NEED MORE RESPIRATORY COMFORT.





--See 2.4.1 for a description of the technology of CPAP and Bilevel S & ST therapy modes featured in the AirCurve 10 ST.

THE ST MODE PROVIDES SLEEP APNOEA PATIENTS WITH FIXED PRESSURE SUPPORT AND ADJUSTABLE BACK UP RATE. THANKS TO ADVANCED SETTING CAPABILITIES, PRESSURE DELIVERY CAN BE FINE-TUNED FOR OPTIMISED BREATHING COMFORT.

--Back-up rate and pressure waveform behaviour defined in the Clinical Requirements Document (internal ref. 10) and defined and tested in the system specifications (internal ref. 8).

--See 2.4.1 for a description of the technology of CPAP and Bilevel S & ST therapy modes featured in the AirCurve 10 ST.

THE ADJUSTABLE BACK-UP RATE ENSURES THE PATIENT GETS THE VENTILATION SUPPORT THEY NEED.

--Back-up rate and pressure waveform behaviour defined in the Clinical Requirements Document (internal ref. 10) and defined and tested in the system specifications (internal ref. 8).




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TICONTROL™ (INSPIRATORY TIME CONTROL) ENABLES CUSTOMISATION TO THE PATIENT’S RESPIRATORY CONDITION AND A NORMAL BREATHING RHYTHM EVEN IN THE PRESENCE OF HIGH LEAKS.


5 LEVELS OF TRIGGER & CYCLE SENSITIVITIES ALLOW FOR FINE-TUNED SYNCHRONISATION BREATH BY BREATH.






--See 2.3.2.6 for a description of the humidification technology featured in the AirCurve 10 ST.









2.7.3 AirCurve 10 VAuto


Claim source: Website THE AIRCURVE™ 10 VAUTO IS AN AUTO-ADJUSTING BILEVEL MACHINE THAT USES THE COMFORT OF BOTH THE AUTOSET™ ALGORITHM AND EASY-BREATHE WAVEFORM IN ITS VAUTO ALGORITHM TO TREAT PATIENTS WITH CHALLENGING OBSTRUCTIVE SLEEP APNOEA CONDITIONS WHO CAN BENEFIT FROM GREATER PRESSURE SUPPORT.


--Bilevel therapy is recommended for adult and paediatric OSA patients if CPAP is not effective or if the patient is uncomfortable or intolerant of high CPAP (2, 8, 15, 16).

--Auto-adjusting therapy algorithm has been found to be non-inferior to standard Bilevel S mode (21).


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--See 2.4.1.2.1 for a description of the Easy-Breathe waveform and 2.4.1.3 for a description of the VAuto therapy algorithm.

THE AIRCURVE 10 VAUTO ADJUSTS THE BASELINE PRESSURE TO HOLD THE AIRWAY OPEN WHILE MAINTAINING A FIXED PRESSURE SUPPORT

--Description of algorithm is defined in the system specification (internal ref. 8) and see 2.4.1.3 for a description of the VAuto therapy algorithm.

THE EASY-BREATHE PRESSURE WAVEFORM MIMICS THE WAVE SHAPE OF NORMAL BREATHING AND REPLICATES IT FOR YOUR BREATHING COMFORT.

--That the Easy-Breathe algorithm is designed to replicate normal breathing is defined in internal ref. 16.


WITH THE NEW OPTIONAL INTEGRATED HUMIDIFIER, HUMIDAIR, YOU CAN ENJOY THE BENEFITS OF HUMIDIFICATION IN ONE EASY-TO-USE SYSTEM. AND WHEN USED WITH THE CLIMATELINEAIR™ HEATED TUBE, YOUR DEVICE HAS BEEN DESIGNED TO AUTOMATICALLY DELIVER THE OPTIMAL TEMPERATURE AND HUMIDITY, FOR THE ULTIMATE COMFORT EXPERIENCE.

--Description of humidifier output is defined in the system specification (internal ref. 8).

--Various user evaluations showed ease of use (internal ref. 33, 44, 38, 40 and 41).




--See 2.3.2.6 for a description of the humidification technology featured in the AirCurve 10 VAuto.

CONTINUOUS LEAK MANAGEMENT ENABLES RELIABLE DELIVERY OF THERAPY PRESSURE WHILE MAINTAINING PATIENT-VENTILATOR SYNCHRONY.


COMPATIBLE WITH UP TO 15L/MIN OF SUPPLEMENTARY OXYGEN IN S AND CPAP MODE AND 4 L/MIN IN VAUTO MODE.

--Oxygen level defined in the Clinical Requirements Document (internal ref. 10) and defined and tested in the system specifications (internal ref. 8).

THE BUILT-IN AMBIENT LIGHT SENSOR ADJUSTS TO THE BRIGHTNESS OF THE ROOM. SO IF YOU NEED TO GET UP DURING THE NIGHT, THE SCREEN’S BACK LIGHT WON’T DISRUPT YOUR BED PARTNER. THE LIGHT ALSO TURNS OFF AUTOMATICALLY, SO YOU CAN SETTLE BACK TO SLEEP WITHOUT DISTURBANCE.







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Claim source: Brochure 1018394r3 internal ref. 7 THE SLEEP THERAPY SOLUTION FOR YOUR NON-COMPLIANT OSA PATIENTS. FEATURING A SEAMLESSLY INTEGRATED CONNECTED CARE SYSTEM, THE AIRCURVE 10 VAUTO IS DESIGNED TO HELP YOU MANAGE YOUR CHALLENGING OSA PATIENTS.

--Purpose defined in Market Requirements Document (internal ref. 9).

--Comprised of bilevel with AutoSet algorithm working on the EPAP as defined in internal ref. 10.



--Bilevel therapy is recommended for adult and paediatric OSA patients if CPAP is not effective or if the patient is uncomfortable or intolerant of high CPAP (2, 8, 15, 16). Typically, a transition from CPAP to bilevel PAP is encouraged when the pressure requirement approaches 15 cm H2O (15, 19, 20).

WITH A NEW STYLISH DESIGN AND EVEN MORE SIMPLICITY, THE NEW AIRCURVE 10 VAUTO PROVIDES AUTO-ADJUSTING PRESSURE TO TITRATE THE UPPER AIRWAY WITH THE REASSURANCE OF FIXED PRESSURE SUPPORT TO THOSE WHO NEED MORE RESPIRATORY COMFORT.





--See 2.4.1 for an overview of the therapy modes featured in the AirCurve 10 VAuto.

--Bilevel therapy is recommended for adult and paediatric OSA patients if CPAP is not effective or if the patient is uncomfortable or intolerant of high CPAP (2, 8, 15, 16).







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IN VAUTO MODE, RESMED’S EASY-BREATHE™ WAVEFORM OFFERS A GENTLE INCREASE AND DECREASE IN PRESSURE IN LINE WITH NATURAL BREATHING FOR MAXIMUM COMFORT.

--That the Easy-Breathe algorithm is designed to replicate normal breathing is defined in internal ref. 16.






--See 2.3.2.6 for a description of the humidification technology featured in the AirCurve 10 VAuto.






2.8 Regulatory history

The AirCurve 10 series has been approved/cleared in the following jurisdictions with the release date stated.

Country/region AirCurve 10 S / ST / VAuto

European Union (EU) 2015 Australia 2015 New Zealand N2015 Canada 2015 USA 2015 Brazil 2015

AirCurve 10 devices are currently CE marked and are on the market.

The AirCurve 10 device range and accessories are classified as Class IIa in Europe according to MDR (Annex VIII):

– Rule 9: “All active therapeutic devices intended to administer or exchange energy [in a non-hazardous way]”;

There have been a number of minor software updates to the AirCurve 10 devices, primarily to improve cybersecurity or CAM performance. The only changes requiring clinical consideration were:


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SpO2 Configuration OTA: an SMS was sent to devices to receive a new configuration command to allow detailed SpO2 data to be collected by AirView when pulse oximeter is connected to an Air 10 Series device within EU. This does not change the data provided by the device, it only allowed the data to be reviewed more easily through AirView. Therefore, no clinical concern.

Humidifier OTA: As discussed in 4.3.2.5, this was a software upgrade to correct humidification error messages. This did not involve any disruption to therapy, and the devices were safe to use, therefore there was no clinical concern.

Sales volume:

As of January 31st, 2019, the global sales volume for AirCurve 10 S, AirCurve 10 ST and AirCurve 10 VAuto is 520,372 units.

2.9 Changes

Not applicable. As this is the first Clinical Evaluation Report to the MEDDEV 2.7/1 rev 4 format, all historic information is included in this current version of the report.

Subject to post-market surveillance activities, the clinical evaluation will be updated in 5 years since the devices of concern are not expected to carry significant risks and are well established.


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3. OVERVIEW OF THE CLINICAL BACKGROUND AND THE “STATE OF THE ART”

3.1 Medical fields

AirCurve 10 devices provide positive airway pressure specifically to patients suffering from OSA due to airway obstructions. Sleep medicine is the medical specialty concerned with the diagnosis and therapy of sleep disturbances and disorders such as sleep apnoea. Sleep medicine interacts with various disciplines, such as respiratory medicine, neurology and cardiology.

3.2 Literature search strategy

A literature search was undertaken to establish the state-of-the-art of bilevel PAP and the current clinical practice of the devices under evaluation as well as comparative devices.

The literature search strategy for OSA and bilevel PAP involves two searches per platform, one search with terms for “bilevel” in the title and “OSA” in any field and vice versa in order to capture literature on “OSA” and “PAP therapy” more generally as well as on “bilevel PAP therapy for OSA” more specifically.

The databases Cochrane Library, PubMed and Embase were searched. Since the speed of innovation for PAP therapy can be considered as slow, a wide time range was used for the search (2000-2018) in order to increase the chance of capturing key literature. Publications types were narrowed to Cochrane reviews, systematic reviews, meta-analyses, practice guidelines and narrative reviews.

The literature searches were undertaken on 19/02/2019. The aim of the review was to establish the state-of-the-art of OSA and bilevel PAP therapy. The literature plan, report, appraisal and analysis are reported in a standalone document internal ref. 21.

The literature search process used by ResMed is detailed in the Quality Management System template internal ref. 22 compliant to the requirements identified in 2.2. ResMed adopts best practise procedures to ensure data integrity during the literature search process. A second qualified person performed and reviewed the literature search.

The following screening criteria was applied to all search results.

Inclusion screening criteria: o Literature must provide insights directly about OSA or bilevel PAP therapy. o Literature on bilevel PAP therapy must be in keeping with the intended use and

intended population of the devices of concern. o Literature must provide insight into the clinical profile of OSA, management of OSA, or

the safety, performance and application of bilevel PAP therapy. Exclusion screening criteria:

o Literature not specifically involving the intended population or the application of the devices of concern.

o Literature reporting outcomes not relevant to the research question of this review (e.g. prevalence of erectile dysfunction in OSA patients).

o A publication type that is not a meta-analysis, systematic review, Cochrane review, critical review or treatment guideline.

o Duplication of search results.

A total of 34 articles met the screening criteria and were included for further review. The outcomes of each individual search are detailed within the literature review document that includes a list of excluded and included articles with reason for exclusion, where applicable internal ref. 21.


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All articles were appraised for quality, relevance and contribution as per as criteria outlined in the clinical evaluation plan internal ref. 4. Based on the variety, wealth and quality of the literature included, the objective of the literature review of establishing the clinical background and state-of-the-art of OSA and bilevel PAP therapy can be reliably addressed.

3.3 Applicable standards and guidance documents

The design of the present device range has taken into account harmonised and international standards as well as guidance documents as detailed in the following table.

Standard/Guidance General Safety & Performance Requirement

Comment

ISO EN 14971:2012 3 The purpose of this international standard is to establish particular requirements for the application of risk management to medical devices. Specifically, ISO 14971 is a nine-part standard which first establishes a framework for risk analysis, evaluation, control, and management, and also specifies a procedure for review and monitoring during production and post-production.

IEC 60601-1:2005/A1:2012

1-8 IEC 60601 is a series of International Standards concerning basic safety and essential performance that are applicable to medical electrical equipment. The purpose of this part of 60601 (IEC 60601-1 Third Ed.) is to outline general requirements of the series of standards.

IEC 60601-1-2:2014 1-8 This part of IEC 60601 (IEC 60601-1-2 Fourth Ed.) applies to the basic safety and essential performance of Medical Equipment (ME) equipment and ME systems in the presence of electromagnetic disturbances and to electromagnetic disturbances emitted by ME equipment and ME systems. The fourth edition of this standard addresses use of equipment outside the hospital or professional healthcare facilities to include home use and special environments.

IEC 60601-1-6:2010/A1:2013

5 The purpose of this part of IEC 60601 (IEC 60601-1-6 Edition 3.1) is to analyse, specify, design, verify and validate usability, as it relates to basic safety and essential performance of ME equipment. This collateral standard addresses normal use and use errors but excludes abnormal use.

IEC 60601-1-11:2015 1-8 This part of IEC 60601 (IEC 60601-1-11 Second Ed.) applies to the basic safety and essential performance of ME equipment and ME systems for use in the home healthcare environment regardless of whether they are intended for use by a lay operator or by trained healthcare personnel. The home healthcare environment includes:

the dwelling place in which a patient lives; and other places where patients are present both

indoors and outdoors, excluding professional healthcare facility environments where operators with medical training are continually available when patients are present.

ISO 10993-1:2009 10 ISO 10993-1 is a standard developed for evaluating the biocompatibility of medical devices. ISO 10993-1 is composed of two components: a normative component which


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requires all the aspects presented in a table to be addressed and an informative component (Annex A) which provides suggestions and considerations for biological assessment of biomaterials. In summary, the standard describes:

the general principles governing the biological evaluation of medical devices within a risk management process;

the general categorization of devices based on the nature and duration of their contact with the body; the evaluation of existing relevant data from all sources;

the identification of gaps in the available data set on the basis of a risk analysis;

the identification of additional data sets necessary to analyse the biological safety of the medical device;

the assessment of the biological safety of the medical device.

IEC 62304:2015 17 IEC 62304 is an international standard that defines software development lifecycle requirements for medical device software. The standard requires all aspects of the software development life cycle to be evaluated, including:

Development Risk management Configuration Problem resolution Maintenance

ISO 80601-2-70:2015 1-8 ISO 80601-2-70:2015 is applicable to the basic safety and essential performance of sleep apnoea breathing therapy equipment. Performance requirements identified in ISO 80601-2-70:2015 can be summarised as follows:

Sound pressure levels emitted by the device shall be measured in accordance with ISO 4871:1996 and ISO 3744:2010 and disclosed accordingly.

The stability in the delivery of static and dynamic airway pressure accuracy shall be verified for each therapy mode.

Maximum flowrate capabilities shall be formally tested and disclosed.

A protection device preventing the airway pressure from exceeding the maximum limited pressure of 30 cm H2O in normal conditions and of 40 cm H2O in single fault conditions shall be provided.

Rebreathing of carbon dioxide shall be minimised to an acceptable level.

ISO 80601-2-74 13 ISO 80601-2-74:2017 applies to the basic safety and essential performance of a humidifier for the different medical uses of humidification and also includes requirements for an active heat and moisture exchanger.

ISO 15223-1:2016 23 ISO 15223-1:2016 identifies requirements for symbols used in medical device labelling that convey information on the safe and effective use of medical devices. It also lists symbols that satisfy the requirements of this document.


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ISO 18562-1:2017 10 Biocompatibility Evaluation Of Breathing Gas Pathways In Healthcare Applications - Part 1: Evaluation And Testing Within A Risk Management Process

Gay P, Weaver T, Loube D, Iber C. Evaluation of positive airway pressure treatment for sleep related breathing disorders in adults. A review by the positive airway pressure task force of the standards of practice committee of the American Academy of Sleep Medicine. Sleep 2006;29(3):381-401

A systematic analysis and grading of peer-reviewed, published clinical studies pertaining to application of PAP treatment in adults by AASM. This paper addresses:

- Efficacy and/or effectiveness of PAP - CPAP titration conducted with full polysomnography

compared with titration with other methods - PAP adherence and compliance - Side effects, efficacy and safety of CPAP - Bilevel for OSA and other nocturnal breathing

disorders. Epstein LJ, Kristo D, Strollo PJ, Jr., Friedman N, Malhotra A, Patil SP, et al. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med. 2009;5(3):263-76.

The Board of Directors of the AASM assembled the Adult Obstructive Sleep Apnea Task Force to review available literature and produce a clinical guideline for the evaluation, management and long-term care of adult patients with OSA. This guideline is meant to assist primary care providers as well as sleep medicine specialists, surgeons, and dentists who care for patients with OSA.

Kryger MH, Roth T, Dement WC. Principles and Practice of Sleep Medicine. 6th ed. China Elsevier, 2016.

Reference includes more than 20 unique sections and over 170 chapters covering every aspect of sleep disorders with evidence-based content.

3.4 Description of medical conditions

Devices in the AirCurve 10 range are intended specifically for OSA patients. OSA is characterized by recurrent obstruction of the pharyngeal airway during sleep, with resultant oxygen desaturation and sleep fragmentation (10, 22-24). The most common symptoms of OSA are daytime sleepiness, nocturnal snoring and ‘choking’ (10).

Individuals with favourable upper airway anatomy may be more able to sustain rhythmic breathing and normal gas exchange, whereas those with highly compromised upper airways may develop complete obstruction (24). In addition to anatomical factors, functional factors such as abnormal ventilatory drive and neuromotor tone contribute to the pathophysiology of OSA (24, 25).

In-laboratory polysomnography (PSG) is often the first-line diagnostic study when OSA is suspected (10,

23, 25). Home sleep apnoea testing with polygraphy (PG) or PSG may be an acceptable alternative for patients who are strongly suspected of having OSA and who do not have medical comorbidities that require more detailed or additional sleep-related measures (2, 10). PG testing can also be carried out with level 3 portable diagnostic devices, which may expedite diagnosis and reduce the costs associated with level 1 in-laboratory PSG (2). However, when OSA is suspected in children, PSG is recommended together with the evaluation of clinical features typical in paediatric OSA such as snoring, laboured breathing during sleep and behavioural or learning problems in combination with sleepiness and hyperactivity (25). A sleep study in children requires well-trained sleep technicians who have experience and skills in child care (25).

Patients who meet criteria for a diagnosis of OSA are traditionally classified as having mild, moderate or severe disease on the basis of the number of apnoeas and hypopnoeas per hour of sleep, namely, the apnoea/hypopnoea index (AHI). For a diagnosis of obstructive sleep apnoea syndrome (OSAS), a


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number of related symptoms also need to be present. The diagnosis of OSA is based upon the frequency of respiratory events during sleep, including AHI and respiratory effort-related arousals (RERAs) as measured by PSG or PG (10). Patients with mild OSA (AHI between 5 and 15) may be relatively asymptomatic or report some daytime sleepiness. Moderate OSA patients (AHI between 15 and 30) are likely to report daytime sleepiness that impacts daily activities. Patients with severe OSA (AHI ≥ 30) are at increased risk for accidental injury from sleepiness (23).

The overall prevalence of OSA (AHI>5) in developed countries has been estimated to be around 5% with men more commonly affected than women (about 2 to 3 times more likely) (23). More recent studies suggest that the prevalence is higher than previously reported (10% in women and 20% in men) (10). The prevalence of OSA is expected to continue to rise due to considerations such as obesity pandemic, improvements in diagnostic technology, and ageing of the population.

There is a strong association between OSA and obesity likely related to the excess weight increasing the risk of pharyngeal airway collapse (10, 26, 27). Natural risk factors of OSA are advancing age, male gender, menopause, family history and craniofacial or upper airway soft tissue abnormalities (10). Additional risk factors identified in some studies include smoking, nasal congestion, and associations with certain medical conditions, such as renal disease, pregnancy, congestive heart failure, chronic lung disease, post-traumatic stress disorder and stroke (10, 22, 24, 28).

OSA occurs in about 1-3% of children (22, 27). Prevalence estimates are about four to five times higher in children with obesity (26, 27). The peak prevalence of OSA in children occurs between 2 and 8 years, due to the development of pharyngeal lymphatic tissue that can lead to adenotonsillar hypertrophy (25). OSA affects children of both sexes equally. Paediatric OSA has some similar features to those seen in adults. At least one obstructive event, of at least two respiratory cycles’ duration, per hour of sleep is required for diagnosis (29). However, children also have unique clinical manifestations of OSA, which can include hyperactivity, emotional difficulties, decreased academic performance and difficulty in concentration (25). In addition to obesity, risk factors for childhood OSA include an impaired neural response, an abnormal central arousal mechanism, congenital and craniofacial abnormalities and a combination of structural defects and neuromuscular factors (25). Like adults, children with severe OSA are at risk for cardiovascular sequelae (27, 29). Even mild OSA and primary snoring have been associated with significant attention impairments and lower memory and intelligence scores in paediatric OSA patients, which is largely reversible with treatment (25).

Evidence consistently suggests that treating OSA is associated with favourable economic outcomes (30), which alludes to the complications that arise when OSA is left untreated. Studies have demonstrated a consistent association between OSA and a number of adverse clinical outcomes ranging from decreased daytime alertness and quality of life to cardiovascular morbidities and mortality and greater medical disability (10, 22, 24). For instance, motor vehicle incidents are significantly more common among patients with OSA than without OSA and there is a well-recognised association of diabetes and insulin resistance with OSA (10, 31). The abnormal breathing and arousal pattern characteristic of OSA may result in haemodynamic, autonomic, inflammatory, and metabolic changes, which, in turn, can contribute to the pathogenesis of a range of cardiovascular diseases such as hypertension, atrial fibrillation, pulmonary hypertension, coronary heart disease, cardiac arrhythmia and heart failure (23, 24, 31).

3.5 Descriptions of available therapeutic options

In most adults, first-line therapy for OSA consists of PAP therapy and behavioural modification, such as positional therapy and weight loss if appropriate. For patients who do not tolerate PAP therapy, common alternative treatment options include oral appliances and surgical therapy. The choice among


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various second-line options depends on the severity of the OSA and the patient's anatomy, risk factors and preference. PAP therapy is one of several treatment options for paediatric OSA patient. For example, watchful waiting is a viable treatment option among paediatric OSA patients.

PAP therapy

PAP therapy is considered the treatment of choice for adult OSA as adopted in evidence-based recommendations and clinical practice guidelines worldwide (2, 8, 32, 33).

A 2006 Cochrane review involving 36 trials and 1,718 patients reported that the available evidence supports the use of PAP therapy as first-line treatment for adults with moderate-to-severe OSA (14). Compared with control, CPAP significantly reduced AHI, improved sleep efficiency, showed significant improvements in objective and subjective sleepiness and improved measures of quality of life (14). This was confirmed in a recent systematic review of 184 clinical studies carried out by a task force of the American Academy of Sleep Medicine (AASM); compared to no treatment, PAP therapy results in a clinically significant reduction in disease severity, sleepiness, blood pressure, and motor vehicle accidents, and improvement in sleep-related quality of life in adults with OSA (34). A subgroup analysis of 5 RCTS suggests that bilevel PAP compared to CPAP similarly improved AHI, sleepiness and quality of life (34).

PAP reduces or eliminates sleep-related respiratory impairments and normalises sleep architecture in most OSA patients (35, 36). PAP is also considered the recommended clinical management for patients with OSA and cardiovascular complications (28). The formalised clinical benefit of PAP therapy is a reduction in apnoeas, hypopnoeas, sleepiness and improved quality of life internal ref. 25. There is also moderate-level evidence showing that PAP devices improve quality of life, increase oxygen saturation and decrease blood pressure (14).

While CPAP delivers a constant pressure through the entire breath cycle, bilevel PAP delivers a pre-set IPAP and EPAP. Bilevel PAP is as effective as CPAP as initial therapy but is not usually used as first-line therapy over CPAP (37). Bilevel therapy is generally recommended for adult and paediatric OSA patients if CPAP is not effective or if the patient is uncomfortable or intolerant of high CPAP (2, 8, 15, 16). In general, a transition from CPAP to bilevel PAP is encouraged when the pressure requirement approaches 15 cm H2O (15, 19, 20). Other indications include the use of bilevel PAP in older OSA patients, OSA patients with hypoventilation or associated comorbidities such as chronic respiratory failure as a result of COPD (8, 38-40).

Common side effects reported with PAP therapy use include pressure on the face, mask discomfort, air leak, dry upper airways, skin breakdown, nasal congestion, aerophagia and pressure intolerance (35, 41). Most side effects associated with PAP therapy can be corrected by interventions such as proper pressure titration, efficient mask fitting and the use of humidification (35). A meta-analysis by the AASM involving 9 RCTs showed that heated humidification improves CPAP-related side effects (34). In paediatric patients, the use of PAP is generally associated with few side effects, which are similar to those observed in adult patients (25).

Side effects left unaddressed can lead to lower the acceptance and adherence rates of PAP therapy. The cut-off point differentiating adherence and non-adherence to PAP therapy is usage of at least four hours per night on 70% of nights over 30 consecutive days. Educational, supportive, and behavioural interventions to improve treatment adherence have met with modest success (42). The choice of optimal interface is also important, because it may influence a patient’s acceptance of PAP therapy (43). Improving patient tolerance of PAP is one of the main driving forces for the development of alternative modes of PAP including bilevel PAP (5). A change in PAP mode may dramatically improve adherence in individual patients (35, 37). However, bilevel PAP has not been shown to improve PAP adherence in


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unselected patients. In a meta-analysis involving 6 RCTs and 286 patients, no statistically significant differences were noted in adherence between bilevel PAP and CPAP (44). Initial patient acceptance was greater for bilevel PAP, but long-term usage in those accepting treatment was similar for both therapy modes (44).

Treatment termination of PAP leads to recurrence of OSA and associated risk factors, such as increased blood pressure (36). There is a general consensus that PAP therapy reduces blood pressure in hypertensive OSA patients and it is considered an adjunctive therapy for hypertension in the practice guidelines (8). Treatment with PAP has been found to improve a number of measures associated with cardiovascular risk, however, the overall evidence on whether PAP reduces cardiovascular events remains equivocal (26, 31, 35, 36).

Behavioural strategies

Behavioural strategies are the conservative approach to OSA management associated with little or no side effects (40, 45). Lifestyle management such as weight loss, cessation of smoking and avoiding caffeinated drinks and alcohol is thus recommended wherever appropriate (2, 41, 46, 47). However, behavioural modifications alone rarely lead to complete remission of OSA and may need to be combined with primary therapy (2, 48).

An increase in body mass index by one standard deviation is associated with a fourfold increase in risk of developing OSA (AHI≥5) (41). Studies have shown that weight loss (bariatric) surgery for extreme obesity in adults and children with moderate to severe OSA reduced AHI, but moderate sleep apnoea persisted (26, 41). The American Academy of Sleep Science recommends that weight loss should be combined with first-line treatment options for OSA such as PAP (2).

Sleeping in a supine position can reduce airway patency and worsen OSA. This may be managed by implementing positional therapy that aims to reduce time spent sleeping in a supine position. Positional therapy may be implemented using measures such as a posture alarm, a backpack with softball inside, pinning a tennis ball to the patient’s clothing or with a wedge pillow (46). Studies have shown that lateral positioning can reduce AHI by eight events per hour (41). However, it is not as effective as PAP therapy in reducing OSA symptoms (40). Positional therapy may improve OSA in some patients and should be encouraged, but not generally relied upon as the sole therapy. The American Academy of Sleep Science recommends positional therapy as an effective secondary therapy for mild OSA or as a supplement to primary therapy (2).

Oral appliances

Guideline and consensus documents have incorporated oral appliances as a treatment option for patients with mild-to-moderate OSA or patients who do not respond to PAP or behavioural strategies (2).

Oral appliances are worn while the patient is sleeping. Mandibular repositioning devices (MRDs) cover the upper and lower teeth and hold the mandible in an advanced position with respect to the resting position, which can improve upper airway patency. Tongue retaining devices (TRDs) are a type of oral appliance that hold the tongue in a forward position to reduce the risk of airway obstruction. TRDs have not been as well studied as MRDs.

Current evidence suggests that MRDs significantly reduce AHI and daytime sleepiness and may also improve blood pressure (40, 45). However, MRDs are generally not as effective in managing OSA as CPAP (14). There is a lack of clinical data on the effectiveness of oral appliances in children with OSA (48); oral appliances are not typically used to manage paediatric OSA.

MRDs can cause side effects such as jaw pains, dry mouth, discomfort, teeth hypersensitivity and increased saliva secretion (40, 49). These side effects are generally mild to moderate in severity and


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usually last a few weeks or less. Occlusal changes are the major long-term adverse effects of oral appliances (40). Contraindications include temporomandibular joint problems and pain (41, 46).

Surgical approaches

Surgical treatment of OSA includes a wide array of procedures and approaches that enlarge and/or stabilize the upper airway. These procedures can be categorized as nasal, upper pharyngeal, lower pharyngeal, global upper airway procedures and upper airway stimulation. Examples include nasal reconstruction, pharyngeal surgeries (e.g. uvulopharyngopalatoplasty), tongue suspension, maxillomandibular advancement, adenotonsillectomy, radiofrequency ablation and tracheostomy (41, 46).

Surgery is rarely indicated as primary therapy in adult OSA patients (40, 41, 45-47, 49). It is generally agreed that most surgical interventions are not as effective as PAP therapy (45). Surgical intervention is recommended as a secondary treatment choice for OSA when PAP therapy or other strategies are unsuccessful or may be considered for patients with mild OSA who have severe obstructing anatomy that is correctible (2).

This contrasts with children, in whom adenotonsillectomy is generally considered the treatment of choice for moderate-to-severe disease in the presence of adenotonsillar hypertrophy (2, 29, 50). Monotherapy with surgery may be insufficient to manage OSA in paediatric Down syndrome patients

(51). In fact, a recent systematic review of the literature concluded that there is little data from RCTs to support the use of adenotonsillectomy in paediatric OSA (52). An increasing number of studies are recommending to attempt alternative management options before surgery (48).

Abad & Guilleminault report on a meta-analysis that showed an overall success rate of 66.4% of multilevel surgery of the upper airway and an overall complication rate of 14.6% (in adults) (41). There are considerable differences in surgical outcomes between the procedures overall. Anaesthesia and surgery are associated with inherent risks that are exacerbated in the setting of OSA in addition to common adverse events like infection, bleeding and pain (41, 46, 49). Other side effects vary according to the procedure. For example, upper airway stimulation of the hypoglossal nerve can lead to fibrosis between the stimulating lead and hypoglossal nerve or hypoglossal weakness (40).

Nasal EPAP

A nasal expiratory positive airway pressure (nasal EPAP) device is a single-use plaster-like device that attaches to the nostrils using an adhesive to create an airtight seal. Nasal EPAP works by increasing positive pressure at the expiratory phase via a mechanical valve that creates high resistance during expiration. Results regarding its effectiveness are mixed (49).

Drug therapy

A variety of pharmacologic agents have been investigated in randomized trials as primary therapeutic agents. The most recent promising results come from a pilot study that showed a significant reduction in airway collapsibility after treatment with desipramine, a tricyclic antidepressant, two hours before bed

(53). However, further studies are needed. To date, no drug has proven to be sufficiently effective in the management of sleep-disordered breathing on OSA (53, 54). A systematic review involving a total of 30 RCTs, 25 drugs and 516 patients concluded that there is insufficient evidence to recommend the use of drug therapy in the treatment of OSA (13). Some pharmacological agents may be a useful adjunct to primary therapy when a contributing cause of OSA is known. For example, the use of nasal steroids and leukotriene antagonists may have a role in mild OSA in paediatric patients (55).

Myofunctional Therapy

Myofunctional therapy involves exercises and other airway training that target dilator muscles in the oral cavity and oropharyngeal structures. Therapy involves activities such as; specific voice lessons, playing musical instruments (including the didgeridoo) and oropharyngeal exercises. This therapy helps


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to decrease airway collapsibility and can lead to a decrease in AHI by up to 50% and up to 62% in children (56). Myofunctional therapy may be a useful adjunct to other alternative therapies for OSA.

Oral Pressure Therapy

Oral pressure therapy consists of a mouthpiece connected by flexible tubing to a console that generates a vacuum of ~50cmH2O that is applied to the oral cavity. The method of action of this therapy is not completely understood but may include vacuum-mediated attenuation of airway collapse during inspiration and activation of upper airway negative pressure reflexes. Oral pressure therapy has been shown to reduce AHI by 43% (56). Common side effects include oral tissue discomfort, dental discomfort and dry mouth (57, 58).

Oxygen Therapy

Oxygen therapy alone is not recommended as a primary or alternative therapy for most patients with OSA. However, there are subgroups of patients with OSA who might benefit for this therapy. Patients with significant cardiovascular disease and only marginally elevated frequency of abnormal breathing events during sleep, but who experience severe oxyhaemoglobin desaturation during these events, might benefit in terms of reduced risk of myocardial ischemia with oxygen supplementation. It may also be considered as an alternative therapy in patients with OSA and significant intermittent hypoxemia who are intolerant of a primary therapy such as CPAP, to minimise potential cardiovascular and metabolic risk. Oxygen may be used as an adjunctive therapy to PAP in patients in whom CPAP or bilevel PAP regimes are effective but in whom hypoxemia persists. There is an absence of high-grade evidence for this therapy and comes with risks including hypercapnia, increase in the duration of apnoea-hypopnoea events and fire risk (57, 59).

Other Alternatives

Other therapies available but that are not used widely and as such not discussed in detail here, include; transtracheal oxygen delivery, high flow nasal therapy, nasopharyngeal stents, venous compression stockings and acupuncture.


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3.6 Hazards

The design of the AirCurve 10 device range has taken into account numerous internationally recognised harmonised standards and relevant guidance documents (3.3). The standards for basic safety and essential performance of sleep apnoea breathing therapy equipment (ISO 80601-2-70:2015) identify design requirements for sleep apnoea breathing therapy equipment, such as, for example, requiring that delivery of dynamic and static airway pressures is accurate and stable in each therapy mode and securing protection against hazards from the device and its components.

ResMed also assesses all hazards, effects and mitigations in order to identify potential hazards associated with the present device range, estimate and evaluate the risks associated with these potential hazards, control potential risks, and continuously monitor the effectiveness of the controls throughout the device’s life cycle. The risk analysis summary for AirCurve 10 devices internal ref. 23 states that the devices have no Essential Performance:

The device has no Essential Performance, as defined by IEC60601-1:2005. This has been determined from the intrinsic safety of the therapy. The basic function of the device is to deliver air to the patient at therapeutic pressures. For the patient groups treated by the device, this therapy is not life supporting. It is considered a low risk to the patient for the device to stop at any time during therapy, or to deliver air at a higher or lower pressure than prescribed. Where there is a risk of excessive overpressure it is mitigated, as described in this risk analysis.

The data recorded and reported by the device is not indicated for use in diagnosis. It may assist management of therapy for compliance, but therapists consider many inputs to their decisions before making significant changes to therapy. Therefore, inaccuracies in data do not present a safety risk.

All hazards in the project risk analysis have been reduced as far as possible. All hazards and applied mitigations have been extracted from the risk analysis summary of the AirCurve 10 internal ref. 23 and are summarised in the table below.

The probability of occurrence of an effect is calculated taking into account all mitigations employed. This occurrence is then ranked/graded as follows:

A severity is assigned to all effects as follows:


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The severity rankings are detailed in the Quality Management System template internal ref. 24 as:

Major

The Level of Concern is Major if a failure or latent flaw could directly result in death or serious injury to the patient or operator.

The Level of Concern is also Major if a failure or latent flaw could indirectly result in death or serious injury of the patient or operator through incorrect or delayed information or through the action of a care provider

Moderate

The Level of Concern is Moderate if a failure or latent design flaw could directly result in minor injury to the patient or operator.

The Level of Concern is also Moderate if a failure or latent flaw could indirectly result in minor injury to the patient or operator through incorrect or delayed information or through the action of a care provider.

Minor

The Level of Concern is Minor if failures or latent design flaws are unlikely to cause any injury to the patient of operator.

From the effects occurrence and severity rankings a Level of Risk following applied mitigations is assigned using:

The acceptability of the level of risk is then ranked according to:


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Risk analysis summary of the AirCurve 10 device range internal ref. 23:

Hazards Effects (clinical risks) Population

Severity class

Mitigated likelihood

Mitigations Acceptability of minimisation of hazards

H1: Excessive Pressure > 50cm H2O for > 1min

Barotrauma (Pneumothorax, Pneumomediastinum or Venous Air Embolism) (E44)

Whole population (P3) Patients at increased risk of pneumothorax, pneumo-mediastinum or venous air embolism (P25)

Major Improbable

M18 Hardware pressure limiting circuit in FG limits mask pressure to 30 cmH20 within 6 seconds & 40 cmH20 within 1 second. M188 High fault pressures result in excessive leak and / or dislodgement of the mask assembly. Furthermore, the device range is not indicated for life support and so pressures as high 50cm H2O are likely to have a very strong arousal effect on the patient who can then remove the mask. M191 The Flow Generator shall perform pressure vs flow vs motor speed plausibility check.

Mitigated risk level: III Risk requiring review.

H2: Excessive Pressure > 30cm H2O

Symptomatic Hypotension (E1) Excessive alveolar ventilation with moderate alkalaemia (E39)

Cardiac failure with normal hydration (P2) Whole population (P3)

Moderate Improbable

M18 Hardware pressure limiting circuit in FG limits mask pressure to 30 cmH20 within 6 seconds & 40 cmH20 within 1 second. M191 The Flow Generator shall perform pressure vs flow vs motor speed plausibility check.

Mitigated risk level: IV Risk adequately mitigated by hazard mitigations.

H3: Excessive Pressure > 10 cmH20

Reduced Cardiac Output (E1)

Cardiac failure with dehydration (P1)

Moderate Improbable Harm from this hazard is controlled by mitigating the faults.


H4: Insufficient Pressure / Pressure Support

Undertreated sleep apnoea (E6) Hypercapnia (E7) Hypoxia (E35)

Whole population (P3)

E6: Minor E7, E35: Moderate

Improbable

M54 Natural urge to breathe causes breathing through mouth when nose is blocked is a reflex response. Full-face mask has anti-asphyxia valve.

Mitigated risk level: IV Risk adequately mitigated by hazard mitigations


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H5: Incorrect Pressure prescribed/ delivered (2 to10cm difference from prescribed/ required)

Undertreated OSA/CSA (E6)


Minor Improbable M216 The device shall be labelled with a symbol to advise the user to read the appropriate instruction manuals before use.


H7: Excessive Air Temperature in Mask (>60C at operating ambient)

External burning (minor/moderate injury) (E8) Airway and or lung burn/toxicity (E17)


Moderate Improbable

M53 A temperature sensor shall detect overtemperature condition within the FG and cause shut-down. M80 Humidifier hardware thermal mitigation turns off heater. M81 Heated tube over temperature cutout and open circuit detection for (balance) on heating elements.


H8: Excessive Enclosure Temperature (>51C external temperature)

External burning (minor/moderate injury) (E8)


Moderate Improbable

M53 A temperature sensor shall detect overtemperature condition within the FG and cause shut-down. M194 Motor stall detection circuit (H/W). M213 While asleep a patient is only likely to touch the applied parts, so there may be prolonged contact only with applied parts. An operator of the device touching other surfaces is awake, so is unlikely to touch most accessible surfaces for longer than 10 seconds, except where disassembly is required (e.g. the humidifier tub for cleaning) in which case a limit of 1 minute is reasonable. This rationale guides test limits for compliance to IEC60601-1:2005 clause 11. No requirement arises. M214 Clarification: the underside of the flow generator and humidifier is not an accessible surface, as the device is placed on a level



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surface for operation. This guides compliance with IEC60601-1:2005 clause 11. No requirement arises.

H9: Electrified Parts (>100 uA leakage current)

Electrocution (death) (E12) Electric Shock (E25)


E12: Major E25: Moderate

Improbable M11 The system shall be certified to IEC60601-1:2005.

E12: Mitigated risk level: III Risk requiring review. E25: Mitigated risk level: IV Risk adequately mitigated by hazard mitigations

H10: EMI to Other Systems

Malfunctioning of medical monitoring, therapy or support equipment (E13)

Nearby patients using medical support equipment (P5) Patient has implanted cardiac device (P18)

Moderate Improbable M189 The system shall be certified to collateral standard IEC60601-1-2 for EMC.


H11: Toxic or allergy causing parts or air

Airway and or lung burn/toxicity (E17)


Moderate Improbable Harm from this hazard is controlled by mitigating the faults that could lead to parts or air causing a toxic or allergic reaction.


H12: Loose/particulate objects in airway

Airway/Lung and or internal injury due to particulates (E10) Asphyxia (E18) Aspiration of Water (E19)


E10, E19: Moderate E18: Major

Improbable

M54 Natural urge to breathe causes breathing through mouth when nose is blocked is a reflex response. Full-face mask has anti-asphyxia valve. M99 Loose or particulate objects (e.g. water droplets) in the upper airways triggers the cough & sneeze reflexes which expels the matter before patient harm occurs in the lungs.

E10, E19: Mitigated risk level: IV Risk adequately mitigated by hazard mitigations

E18: Mitigated risk level: III Risk requiring review


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H13: Smoke/fumes in Airway

Airway and or lung burn (E17) Asphyxia (E18)


E17: Moderate E18: Major

Improbable

M50 Under worst case conditions, does not cause fire without supplemental oxygen. M53 A temperature sensor shall detect overtemperature condition within the FG and cause shut-down.

E17: Mitigated risk level: IV Risk adequately mitigated by hazard mitigations E18: Mitigated risk level: III Risk requiring review

H14: Contaminated parts or air

Microbial cross infection (E20)


Moderate Improbable Harm from this hazard is controlled by mitigating the faults that could lead to contaminated parts or air.


H15: Design causing physical injury

External physical injury (bruising, cuts) (E22)


Moderate Improbable Harm from this hazard is mitigated by design. Mitigated risk level: IV Risk adequately mitigated.

H16: Incorrect Humidification

Nasal drying with mucosal friability and bleeding (E40)


Minor Improbable

M168 Patients are insensitive to inaccurate humidification; many don't need humidification and many only develop symptoms of dryness if the humidification is altogether absent..


H17: Fire with supplemental oxygen

External burning (minor/moderate injury) (E8) Asphyxia (E18)

Population using supplemental oxygen (P7)

E8, E10, E17: Moderate E18, E24: Major

Improbable

M51 The FG has been verified for use with supplemental oxygen flowing at up to 15 L/min. M52 In a single fault condition where supplemental oxygen has been left on with the FG not blowing, the FG will not cause ignition if it is subsequently restarted. M194 Motor stall detection circuit (H/W).

E8, E10, E17: Mitigated risk level: IV Risk adequately mitigated by hazard mitigations


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Airway/Lung and or internal injury due to particulates (E10) Airway and/or lung burn (E17) Burns leading to serious injury or death (E24)

E18, E24: Mitigated risk level: III Risk requiring review

H18: Fire without supplemental oxygen

External burning (minor/moderate injury) (E8) Asphyxia (E18) Airway/Lung and or internal injury due to particulates (E10) Airway and/or lung burn (E17) Burns leading to serious injury or death (E24)

Patient not using supplemental oxygen (P26)

E8, E10, E17: Moderate E18, E24: Major

Improbable

M50 Under worst case conditions, does not cause fire without supplemental oxygen. M53 A temperature sensor shall detect overtemperature condition within the FG and cause shut-down. M194 Motor stall detection circuit (H/W).

E8, E10, E17: Mitigated risk level: IV Risk adequately mitigated by hazard mitigations

E18, E24: Mitigated risk level: III Risk requiring review

Hazards associated with PAP for OSA identified in the literature are discussed in section 4.3.2.


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3.7 Types of users

ResMed PAP devices are intended for use by patients and carers in the home environment, by qualified, trained personnel in the hospital environment and equipment suppliers in the sales environment.

Parents, carers and patients receive their knowledge in relation to OSA and PAP from sleep clinics, equipment suppliers and device labelling. Qualified personnel have medical or science backgrounds with prior knowledge and/or training in the principles of PAP to treat OSA. Equipment suppliers (e.g. durable medical equipment (DME) suppliers, home health care (HHC) providers, distributers, sales staff) receive basic training in relation to OSA and PAP and how to trouble shoot. User profiles can be grouped as follows:

The following table defines the user profiles:

Profile Group Description

Lay Operator/ Non-clinical

Patient

Parent

Carer

Clinical

Physician

Sleep Technologist

Sleep Scientist

Respiratory Therapist

Physiotherapist

Nurse

Equipment suppliers

DMEs

HHCs

Distributers

Sales staff

Operator Profile

Patient

Education: Knowledgeable on how to use the device (Patient level) through education provided by clinicians and equipment suppliers and user guides.

Role: User of the PAP equipment.

Availability: Using PAP while asleep.

Parent / Carer

Education: Knowledgeable on how to use the device (Patient level) through education provided by clinicians and equipment suppliers and user guides.

Role: Help patient apply and remove PAP as well as trouble shooting during the night and cleaning equipment.

Availability: As required by patient.


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Physician

Education: Medical background. Knowledgeable on OSA, mode of operation of PAP, and how to use the device through study and/or on the job training and clinician guides.

Role: Tasks include:

o patient assessment, diagnosis and ongoing assessment (as required)

o analysing/interpreting sleep studies

o signing off on patient reports

o prescription of products

o setting up devices and fitting of masks (involvement may vary here)

Availability: Sleep clinics, hospital clinics and wards

Sleep Technologist / Nurse / Sleep Scientist / Respiratory Therapist / Physiotherapist

Education: Science background. Knowledgeable on OSA, mode of operation of PAP, and how to use the device through study and/or on the job training and clinician guides.

Role: Tasks include:

o reviewing new patients

o providing education and support to patients,

o setting up and fitting equipment to patients,

o recording, monitoring and overseeing diagnostic and titration studies

o interpreting and scoring recorded data from sleep studies and flow generators,

o writing summary reports,

o troubleshooting with patients,

o writing scripts,

o reprocessing and cleaning equipment,

o carrying out equipment maintenance

o discussing the progress of patients with physicians,

o organising account payment

Availability: Sleep units, hospital clinics and wards.

Equipment suppliers

Education (either):

o Basic knowledge on OSA and knowledgeable on mode of operation of PAP through on the job training and clinician guides, or;

o Clinical background with science or medical training with in depth knowledge of OSA and PAP through study and/or on the job training and clinician guides.

Role: Tasks may include:


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3.8 Diverging opinions of professionals as to the use of the different medical options

PAP therapy is considered the treatment of choice for OSA as adopted in evidence-based recommendations and clinical practice guidelines worldwide.

The American Association of Sleep Medicine (AASM) acknowledges PAP for moderate-severe OSA as a Standard Practice, which is defined as “a generally accepted patient-care strategy that reflects a high degree of clinical certainty” (2). In a recent update of the evidence the AASM recommended that “clinicians use PAP, compared to no therapy, to treat OSA in adults with excessive sleepiness. (STRONG)” (32). A number of systematic reviews have concluded that PAP therapy significantly reduces disease severity, sleepiness, blood pressure, motor vehicle accidents, and improves in sleep-related quality of life in adults with OSA (14, 34) and internal ref. 21.

A technology appraisal guidance carried out by the UK’s National Institute for Health and Care Excellence (NICE) in 2012 concluded that:

Continuous positive airway pressure (CPAP) is recommended as a treatment option for adults with moderate or severe symptomatic obstructive sleep apnoea/hypopnoea syndrome (OSAHS).

CPAP is only recommended as a treatment option for adults with mild OSAHS if (1) they have symptoms that affect their quality of life and ability to go about their daily activities, and (2) lifestyle advice and any other relevant treatment options have been unsuccessful or are considered inappropriate.” (NICE technology appraisal guidance 139) (33).

The American Academy of Sleep Medicine (AASM) has published practice parameters on the indications for PAP in the treatment of OSA in 2006 (8) and 2008 (15). Recommendations are assigned a ranking group based on the supporting evidence with ‘Standard’ reflecting the highest degree of clinical certainty, ‘Guideline’ reflects a moderate degree of clinical certainty, and ‘Option’ reflecting

o setting up patients for take home diagnostic studies

o setting up and fitting equipment (masks) to patients

o providing education and support to patients

o selling PAP devices to patients

o providing education to patients

o troubleshooting with patients.

o reprocessing and cleaning equipment,

o carrying out equipment maintenance

o organising account payments

o some equipment suppliers would be dedicated to OSA patients while others may sell a wide range of medical equipment and deal with a variety of patients and want to complete sales quickly and efficiently.

Availability: DMEs, HHCs, distributers, shop outlets during business hours.


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agreements that were reached in a standardised consensus process based on available information. Relevant recommendations for bilevel PAP include:

– Bilevel PAP is an optional therapy in some cases where high pressure is needed and the patient experiences difficulty exhaling against a fixed pressure or coexisting central hypoventilation is present (Guideline) (8)

– If CPAP is not effective or if the patient is uncomfortable or intolerant of CPAP, the adult or paediatric patient may be switched to bilevel PAP (Option) (15)

Adenotonsillectomy is generally recommended before PAP therapy in paediatric OSA patients. However, there is high-level evidence to support PAP therapy in the treatment of childhood OSA if adenotonsillectomy is not preferred or is unsuccessful as cited in Clinical Practice Guidelines by the American Academy of Paediatrics (60).

3.9 Unmet medical needs

There are challenges in the diagnosis of patients with minimally symptomatic or asymptomatic OSA. Routine health screenings are relied upon to help diagnose this subgroup of OSA patients. Women in particular are at high risk of being misdiagnosed or underdiagnosed (61). A growing body of evidence is addressing the differences in the physiology and presentation of OSA in women (62).

Once diagnosed, OSA is treatable in most patients. A meta-analysis of 12 studies concluded that PAP therapy can treat OSA symptoms across a diverse range of populations (country, gender, BMI and OSA severity) (63). Generally speaking, PAP should be able to stabilise any upper airway. Patients with craniofacial abnormalities that prevent the correct use of PAP masks are a special exception. Such patients are often directed to alternative treatment options.

Adherence to PAP treatment is the largest factor impacting on its effectiveness. The most widely recognised criterion for compliance is usage of a PAP device for >4 hours per night on at least 70% of nights. Based on this definition, between 29% and 83% of PAP users are considered noncompliant (64). Telemonitoring and patient engagement tools have been shown to significantly improve treatment adherence when compared to standard care (17, 18).


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4. MEDICAL DEVICE/S UNDER EVALUATION

4.1 Type of evaluation

Article 61 §10 of MDR’s 2007/47/EC Directive states that:

Without prejudice to paragraph 4, where the demonstration of conformity with general safety and performance requirements based on clinical data is not deemed appropriate, adequate justification for any such exception shall be given based on the results of the manufacturer's risk management and on consideration of the specifics of the interaction between the device and the human body, the clinical performance intended and the claims of the manufacturer. In such a case, the manufacturer shall duly substantiate in the technical documentation referred to in Annex II why it considers a demonstration of conformity with general safety and performance requirements that is based on the results of non-clinical testing methods alone, including performance evaluation, bench testing and pre-clinical evaluation, to be adequate.

ResMed has deemed that the demonstration of conformity with General Safety and Performance Requirements based on clinical data is not appropriate. PAP therapy for OSA has a long history and is based on well-established technology and consistent claims with no significant innovative aspects. All PAP devices work by simple physiological mechanisms that involve generating low pressures of air delivered through the nasal or oronasal passages that keep the airway open during sleep. The device/body interaction is thus circumscribed to the resulting pneumatic splint along the pharyngeal airway.

Performance criteria and safety mitigations are clearly defined in harmonised standards (ISO 80601-2-70:2015), which have been incorporated into the design of the AirCurve 10 range internal ref. 1. As such, ResMed is able to demonstrate compliance with the General Safety and Performance Requirements by meeting the requirements of these internationally recognised standards.

Despite this, to validate the ongoing safety and performance of the PAP devices on the market as per MDR Annex XIV §1, this clinical evaluation will identify, appraise and analyse all relevant clinical data. This includes any premarket clinical investigations, PMCF studies, postmarket reports and usability evaluations undertaken by ResMed

The clinical evaluation of the AirCurve 10 range also draws on all pertinent data from the literature on the devices for their intended purpose as well as on PAP therapy in general with regards to safety, performance and clinical background.

These data, together with the results of the risk analysis, are deemed sufficient to support the General Safety and Performance Requirements of ResMed’s bilevel PAP devices for OSA.

4.2 Demonstration of equivalence

Not applicable; equivalence is not being claimed between the device family covered in the clinical evaluation and other benchmark devices. The devices under evaluation have been designed and manufactured in accordance with internationally recognised standards applicable to home CPAP devices.


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4.3 Clinical data generated and held by the manufacturer

ResMed has deemed that the demonstration of conformity with the General Safety and Performance Requirements based on clinical data for the present device range is not appropriate. However, as mentioned above, to validate the ongoing safety and performance of the PAP devices on the market, the clinical evaluation will identify, appraise and analyse all available clinical data relevant to the devices as per MDR Annex XIV §1.

As specified in the clinical evaluation plan internal ref. 4, all clinical data generated and held by ResMed will be considered suitable, thus no explicit appraisal criteria on its relevance was predefined. The clinical evaluation includes all internally generated clinical data by default. The criteria for determining the quality and contribution of internally generated clinical data as well as the results of the appraisal are outlined in section 4.5.1. The following sections aim to provide an overview of internal clinical activities and their main outcomes.

4.3.1 Premarket clinical investigations

No premarket clinical investigations involving the devices under evaluation additional to usability evaluations (4.3.3.3) and patient model bench test reports (4.3.3.4) were undertaken by ResMed.

4.3.2 Clinical data generated from risk management activities and PMS programmes

4.3.2.1 PMCF studies

As outlined in the PMCF report internal ref. 57, Five retrospective cohort studies analysed cloud data from the present device ranges’ telemonitoring (AirView) and patient engagement tools (myAir) confirm the ongoing effectiveness of PAP therapy in the patients’ home and suggest a positive effect of patient engagement on treatment adherence. Future PMCF activities are captured in the PMCF plan internal ref.

58.

A retrospective analysis involving a German cohort matched 500 patients in proactive telemonitoring care with 500 patients on additional patient engagement based on sex, age, device type, mask type and insurance type (18). All patients were users of an AirCurve 10 device or an AirSense 10 device (home CPAP device not in the scope of this clinical evaluation) and data on the full AirCurve 10 range was collected. The effect of the additional patient engagement tool on device usage was analysed over a 180-day period. The proportion of nights with device usage of at least 4 hours per night was 77 ± 25% in the patient engagement group versus 63 ± 32% in the telemonitoring only group (p < 0.001). Therapy termination occurred less often in the patient engagement group (p < 0.001). Mask leak was also significantly lower in patients using the patient engagement tool. This study also reported low AHI values in patients receiving PAP in both the patient engagement group and the usual care monitoring group (both mean AHI < 5) (18).

A similar study was conducted in a US cohort (17). 42,679 patients using the patient engagement tool with telemonitoring were matched 1:2 with 85,358 patients using telemonitoring only (devices from AirCurve 10 and AirSense 10 range, same as above). Additional patient engagement was associated with more patients achieving adherence criteria (device usage of at least 4 hours per night) with 87.3% compared to usual care monitoring with 70.4% (p < 0.001). Average device usage was significantly


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increased: 5.9 hours per night versus 4.9 hours (p < 0.001). AHI was consistently low in both groups (< 5) (17).

The emergence of central sleep apnoea (CSA) during PAP therapy is highly variable for the first 90 days of treatment. For those patients that have persistent or treatment-emergent CSA treatment adherence might be improved by switching to adaptive servoventilation (ASV). Device data was analysed in 198,890 patients (from the AirCurve 10 and AirSense 10 range), involving a total of 189,724 PAP users, 8,957 ASV users and 209 patients that switched from CPAP to ASV (65). 90-day adherence rates were compared between the groups. At 90 days, adherence rates were 73.8% and 73.2% in the CPAP only and ASV only groups. In the Switch group, CPAP adherence was 62.7%, improving to 76.6% after the switch to ASV. The results of the data before and after a switch from CPAP to ASV provides insight into the role of residual or treatment-emergent CSA in contributing to worse adherence during CPAP (65).

In a recent study, the effects of switching from CPAP/APAP to bilevel PAP were analysed in 1,496 non-compliant OSA patients (66). All patients were non-compliant within 90 days of starting CPAP/APAP (based on device usage <4 h/day on 70% of nights over 30 consecutive days). 30.3% of patients used CPAP, 62.3% used APAP and 7.4% used both CPAP and APAP before switching to bilevel PAP (with either an AirCurve 10 S or an AirCurve 10 VAuto). About half of patients started bilevel PAP in spontaneous mode (47.8%) and half in VAuto mode (52.2%) (see 2.4.1 for more detail on therapy modes). Device usage significantly increased after switching to bilevel therapy by an average of 0.9 h/day (p<0.001). Overall, 56.8% of patients who were non-compliant with CPAP/APAP achieved compliance criteria after switching to bilevel PAP. Residual AHI also improved significantly after the switch to bilevel PAP from an average AHI of 4.9 to 4.0 (p<0.001) (66).

In an analysis on CPAP compliance of over 2 million patients (67), high levels of adherence were found in patients using an AirSense 10 (or AirCurve 10) device. Among patients initiating PAP therapy, 75% achieved the generally accepted compliance threshold (at least 4 hours of use in >70% of nights during 30 consecutive days over a 90-day period). This adherence rate compares favourably with other chronic medical therapies. Mean daily usage was 6.0 ± 2.0 hrs on days used with the median percentage of days used being 93 for an overall mean daily usage of 5.2 ± 2.5 hrs. Median residual AHI was < 5/h and mask leak was within acceptable levels (67).


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4.3.2.2 PMS reports, including vigilance reports and trend reports

4.3.2.2.1 Trend reports

The Product Field Performance (PFP) is a metric used by ResMed to indicate when the quality of a product has improved or worsened over time, in order for ResMed to take appropriate actions. The PFP metric shows the monthly complaint rate per device in the field. For example, 0.1% indicates that 1 in 1000 devices generated a complaint in that month. This metric includes ALL field complaints regardless of cause – a substantial proportion of field complaints may not be considered device failures after investigations of the complaints have completed. The overall product field performance for the AirCurve 10 devices under evaluation are shown in Figure 8.

Figure 8. Product Field Performance – AirCurve 10 S/ST/VAuto

Sales figure from launch to 28th Feb 2019 (inclusive):

Product Category Sales Volume

(units)

AirCurve 10 S 106121

AirCurve 10 ST 53288

AirCurve 10 VAuto 398124


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As can be seen in Figure 8 above, there is a considerable spike in complaints in the first months after product launch followed by a downward trend over time. An initial high level of complaints coupled with gradual improvement over time is a commonly observed trend with newly launched devices; there are three primary reasons for this:

1. Following a product launch, ResMed received a wealth of feedback users were familiarising themselves with the new product. Some of these complaints were user-related and warranted more training or education, while others reflected genuine quality issues.

2. At around the middle of 2015, we encountered some issues with product design and manufacturing, specifically with noise and start/stop button issues, which is reflected by the peak in complaint rate (details of the issues are discussed in the next section below).

3. An inherent outcome from this metric is high sensitivity in the initial months due to a small installed base. As the total number of devices in the field is the denominator in the PFP calculation, this metric is more sensitive when there are few devices on the field, leading to early spikes and dips.

Based on close monitoring, analysis and trending of issues performed by the complaints handling and quality analytics teams, there are issues which have been escalated from complaints over the life of the products.

The most common issues observed with AirCurve 10 devices and accessories include:

(Note: The AirCurve 10 shares the same base unit as other AirSense 10 class of products. Hence the AirCurve and AirSense platforms will exhibit similar issues)

Discoloured Tubs

Description:

Complaint received for brownish discolouration on the bottom of HumidAir tub and reported under PR815699 and PR789311. Based on visual investigation a discoloured ‘mark’ was found on the tub plate, and chemical analysis performed identified this to be iron oxide and iron silicate.

There are several probable contributors to the root causes are: 1. Cleaning process of the tub – as variation in the process parameters could potentially

affect the tub plates surface finishing and flatness. 2. User’s setting of humidification level or the environment humidity would potentially play

a part in contributing to the higher temperature gradient across the plate surface. 3. Distilled and deionised water

Risk assessment were carried out and issue was deemed acceptable. Improvement were made to Tub Plate Specification to include metal pressing, cleaning and finishing details.

Reference: T1-00110

Clinical expert comment: this does not represent a patient safety risk. Tub discolouration is an inconvenience but does not result in patient harm.

Missing accessories or parts that were supposed to be supplied with AirSense 10 devices


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Description:

Complaint were raised for investigation for missing components of AirSense class of products. Based on the field complaints from Aug’14 to Jul’15, the top 4 identifiable missing components were missing power cords, missing humidifier tubs, missing PSU and missing tubing.

Risk was assessed and deemed as acceptable. Missing components will result in customer dissatisfaction as they were unable to use the devices.

The packaging station is a manual operation and from the investigation findings, 2 probable root causes were identified.

1. Operators’ experience – operators relied on their experience by gauging the weight of the carton to determine missing components.

2. Components not scanned. 3. Poor clarity of the assembly procedure and operator’s boundaries could also

potentially lead to operators’ error like missing component. The following improvement were implemented to improve this issues:

1. Introduce weighing scale after packing process 2. Clarifying Assembly Procedure to clearly define the responsibility of each operator.

Reference: T1-00183

Clinical expert comment: this does not represent a patient safety risk. This was a quality issue that would not result in patient harm. Importantly, preventative measured were applied by ResMed to address this issue.

Leaking Tubs

Description:

Complaint was received from Europe for humidifier tub leaking water, and reported under PR819985. Based on the actual field occurrence and severity of the reported fault, a risk assessment was performed and deemed as acceptable risk. It was observed that the failed tubs indicated that the failure arose from a mixture of both supplier process errors and customer errors. An intensive fishbone diagram was conducted and a few probable root causes were identified:

1. Supplier - Poor welding, attributed to the weld nest and the horn at the supplier’s base 2. Supplier – Twisted seals, assembly process of tub at the supplier base 3. Customer – volatile chemical used 4. Customer – dishwashing chemicals used to clean 5. Customer – physical abuse (eg: dropped tub and knife damage)

Several improvements were implemented, namely: A. To address Root Cause 1

‐ redesign of the nest at supplier’s end ‐ implement weld monitoring software, establishing control charts and

quarantining ‘out of control’ products. B. To address Root Cause 4

‐ monitor effectiveness of the welding monitoring software for detection of twisted seals.


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‐ Include visual check for twisted seals after welding process at the supplier’s end.

Reference: T1-00188

Clinical expert comment: this does not represent a patient safety risk. This was a quality issue that would not result in patient harm. Importantly, the information supplied by ResMed was updated to address this issue.

Whistling Tubs

Description:

Complaint was reported under PR886056 for tubs whistling during therapy. The risk was assessed and deemed acceptable as it does not yield any risk to the patient, it will only impact the user’s experience. It was discovered that whistling occurred at the silicon seal interface between the upper and lower tub shell junction. Upon investigation, it was discovered that the silicon seal had a ripple in the membrane that would oscillate under therapy pressure. The ripple was identified as a manufacturing defect.

Corrective action was taken suspend hot runner tooling from supplier’s production, and converting them to cold runner tooling.

Reference: T1-00213

Clinical expert comment: this does not represent a patient safety risk. Noise is an inconvenience but does not result in patient harm.

On/Off button Failure

Description:

Complaint was reported under PR882192, in Europe, for On/Off button malfunctioning.

The safety risk for this complaint was assessed and deemed acceptable. It will result in customer dissatisfaction.

From a thorough root cause analysis, the failure mode on both ALPS and Omron switches were related to the breakdown of the 4 heat stick plastics that hold the plastic body to the metal structure. There is a lack of hard-stop feature in the User Interface design or button design which would prevent such a failure.

Improvement measures were taken to quality and replace with new switches from ALPS that has a metal backing which proved to be 2-3x stronger than current switches. The metal backing on the switch will act as a hard-stop to the User Interface.

Reference: T1-00235

Clinical expert comment: this does not represent a patient safety risk. Given that the ResMed PAP devices are used to treat OSA, any interruption in therapy due to this issue would not result in patient harm.

Faulty 90W power supplies returned with no output


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Description:

A substantial number of Air10 90W power supplies (R370-7296) has been returned with no output.

The safety risk for the complaint was and considered to be acceptable.

Upon investigation, the reason for the failure in these units were due to a capacitor short circuit (C4) that activates the safety fuse on the mains input. The fuse had interrupted the mains input and safely shuts down the power supply. Hence, the C4 failure and subsequent fuse operation will consistently result in an inactive and safe power supply condition.

The cause for this capacitor failure has been identified to be due to higher operating temperature, which was a result of an increase in Dissipation Factor (related to equivalent series resistance) due to batch to batch component variations. Higher operating temperature would lead to premature (wear-out) failure.

Corrective Action were implemented to replace the capacitor with a part that consistently has a lower Dissipation Factor and thus a lower operating temperature.

Reference: CAPA-0173

Clinical expert comment: this does not represent a patient safety risk. Given that the ResMed PAP devices are used to treat OSA, any interruption in therapy due to this issue would not result in patient harm.

Inlet seal deformation

Description:

A number of devices were returned from the field for high leak or noise. Investigation were conducted for this issue under PR849083, and identified it to be a problem with the inlet seal.

Based on the severity and occurrence, the safety risk associated was assessed and considered as acceptable.

A thorough root-causes analysis was conducted for the deformed intel seal, and the probable causes are:

1. Due to manufacturing packing process that could potentially lead to the deformation of the inlet seals. High production yields can lead to higher packing loads as the packing process is wasn’t controlled.

2. Design of the inlet seal to the tub interface doesn’t allow for variation in misalignment. Due to the misalignment and in combination of the deformed seals, wrinkling can occur easily due to the uneven loading condition.

Measures were taken to improve the design of tray packaging to mitigate the occurrence due to manufacturing packing process.


Clinical expert comment: this does not represent a patient safety risk. This was a quality issue that would not result in patient harm.

Wrong power cord supplied with device


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Description:

Complaint was reported in US, and recorded under PR1260103, that a number of devices received at the US DME’s end were packed with EU power cord instead of the required US power cord.

The safety risk associated with this complaint was assessed and considered to be low risk to patient. It would bring upon customer dissatisfaction as the customer won’t be able to use the devices as intended.

Upon investigation, the following root causes were identified: 1. KanBan Rack wasn’t topped up, hence an intermediate KanBan was used. This

allowed for the possibility of power cords mixing up, as the intermediate KanBan contains various types of power cord.

2. Warehouse does not accept returns for partial boxes and material handlers are required to store unused power cords in the intermediate KanBan. Hence any material in the intermediate KanBan may be mixed due to mishandling.

3. Supplier didn’t palletise the boxes of power cords. Therefore, there is possibility of external warehouse mishandled/ incorrectly palletised power cords due to the boxes being similar on the exterior.

Several improvement measures were implemented: ‐ Warehouse material handlers will ensure KanBan for power cords are

continually topped up so that the production material handlers will be picking up the power cords from KanBan racks instead of warehouse.

‐ Production team have been trained to ensure that no intermediate KanBan trolley for power cords are used within the packaging line. This will enable material handlers to return partially used lots back into KanBan location rather than storing them in the intermediate KanBan trolley.

‐ Implemented a colour coding for box straps to create distinction between different power cords, so that forwarding warehouse are able to palletise the boxes according to the strap colours.



Loose CAM PCBs

Description:

A substantial number of out of box failures (OOBF) are being reported on AirSense 10 AutoSet devices from customers in Japan due to a rattling noise coming from the devices when shaken as part of their acceptance testing. When the devices were returned for investigation, it was discovered that the CAM PCB boards were separated from the side panel resulting in this rattling sound.


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The safety risk associated with this complaint was assessed and considered acceptable. It will result in customer dissatisfaction as there will be undesired rattling noise when the device is being shaken.

Investigation showed that the CAM boards with the failure are consistently not clipped in for one particular Locking peg. As per R370-602, AirSense 10 Base unit Assembly procedure and R370-669 AirSense 10 Flat BOM Assembly and Packing Procedure, there is currently a requirement to ensure both pegs be properly clipped in, which eliminates the possibility or a process deficiency. The frequency at which the issue occurs also suggests that there are no batch related issues. Further investigation showed that one particular operator had been contributing the most to this failure, and this suggested that it is an operator error.

The improvement measures were still in progress to be implemented. And in the mean-time, Temporary deviation was implemented to shake devices 5 times before testing / packing, allowing operators to detect the assembly error when it manifests.



Missing AirSense 10 tubing elbow

Description:

Complaint were reported from a customer that 40units of AirSense10 devices (Product Code: 37236) are missing with elbow (Product Code: 37394). A Global On-Hold meeting (OH-2018-52) was initiated for this.

The risk assessment was assessed and there is no patient safety risk due to the missing elbow. In this issue, the user will still be able to connect the breathing tube directly to the device but wouldn’t be able to turn around the axis. The assembly for the slimline tube is part of the packaging process which was performed offline. And the assembly procedure was properly documented in AirSense 10 Packaging Procedure Rev18. And the overview of the flow will be as below:

Pick tubing >> fold tubing >> Insert AirSense 10 tubing and elbow into bag >> Seal the bag

Based on last 12 months of complaint data, there was only 1 incident of missing elbow complaints. And it was reported from another manufacturing site in ResMed. Hence the most probable root cause was that the elbow had been unintentionally left out during the slimline tube assembly

Improvement had been implemented to the work instruction in Packaging Procedure R370-640 to include visual check on elbow presence before sealing of bag and a secondary visual check for elbow presence (by another operator) before packing into carrying bag.



Noisy motor


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Description:

There has been an increasing trend in returns of noisy devices from recently build Air10 devices. Investigation has confirmed the increased in motor noise were due to lack of proper application of the damping grease within the blower assembly and the differences in magnet manufacturing processes between Rotor Suppliers



4.3.2.2.2 Vigilance reports

As a manufacturer, ResMed adheres to and maintains regulatory obligations globally, and submits vigilance reports according to the regulatory reporting requirements in all countries for which ResMed has regulatory approval.

A total of 3 vigilance reports were submitted in the period between November 2014 and November 2018, to the U.S Food & Drug Administration (FDA).

As shown in Figure 9 below, 2 injury reports were submitted for desaturation and stroke, and 1 report was submitted for fire incident.

Figure 9. Breakdown of reports submitted for different complaint type

The summary of each vigilance reports are listed below:

1. Report Number: 3004604967-2016-01210

Model: AirCurve 10 S


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Event Description: It was reported to ResMed that a patient treated with an AirCurve 10 S was hospitalized. The device was reported to have shut off during use causing the patient's saturation to drop.

Date of Awareness: 11/10/2016

ResMed’s Investigation: An extensive engineering investigation was performed on the returned unit.

External and internal inspection of the device and the review of the device error logs found no abnormalities.

Functional testing of the device showed that the device was operating within specifications.

The investigation did not find any device malfunction that could have contributed to the reported issue.

Overall rate of issue at the time of investigation is 0.00891% (based on 3,838,784 units sold).

2. Report Number: 3004604967-2017-00064

Model: AirCurve 10 VAuto

Event Description: It was reported to ResMed that a patient treated with an AirCurve 10 VAuto had a stroke.


ResMed’s Investigation: An extensive engineering investigation was performed on the returned unit.

External and internal inspection of the device and the review of the device error logs found no abnormalities.

Functional testing of the device showed that the device was operating within specifications.

The investigation did not find any device malfunction that could have contributed to the reported issue. The complaint information was reviewed by a ResMed Clinical Specialist. Per their review, clinically, a stroke is not associated with CPAP therapy use. Thus, there was no relationship between the device to the reported incident.

Overall rate of issue at the time of investigation is 0.00003% (based on 3,838,784 units sold).

3. Report Number: 3004604967-2018-00612

3007573469-2018-00613


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Model: AirCurve 10 VAuto

Event Description: It was reported to ResMed that an AirCurve 10 VAuto device allegedly caught fire.


ResMed’s Investigation: The device has not been returned to the manufacturer, therfore, ResMed is unable to determine if a device fault contributed to the incident. ResMed is in communication with the reporter to obtain additional information regarding the event details and requested the unit be returned so that an extensive engineering investigation can be performed. If the device is returned, ResMed will provide a follow-up report with additional information.

Overall rate of issue at the time of investigation is 0.00033% (based on 600,245 units sold).

A total of 8 vigilance reports were submitted in the period between November 2014 and November 2018 for bi-level accessories. As shown in Figure 10, two reports were submitted to the U.S Food & Drug Administration (FDA) for fire/flame complaints (no patient injury was reported), and another two non-injury reports (for charging issues with RPSII) were also submitted to the FDA. Two reports were submitted to the National Agency for the Safety of Medicines and Health Products (ANSM - France) for torn tubing issues. Reports of power and charging issues with the RPSII were also submitted to National Supervisory Authority for Welfare and Health (Valvira – Finland) and both FDA and Pharmaceuticals and Medical Devices Agency (PMDA - Japan) respectively.

Figure 10. Breakdown of reports submitted by regulatory bodies and complaint type (accessories)


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The summary of each vigilance reports for AirCurve 10 accessories are listed below:

(Note: The number of vigilance reports submitted for accessories is higher compared to AirCurve 10 devices, because AirCurve and Lumis platforms share the same base unit as AirSense 10 platform. As a result, the accessories can be used across these three platforms, and it is not possible to determine which platform the accessories were used for. Some AirCurve accessories such as RPSII are also compatible with other ResMed products such as Astral and Stellar ventilators. Therefore, while the vigilance reports may have been submitted for RPSII specifically, they were not necessarily used for AirCurve devices).

1. Report Number: 3004604967-2015-00178 (LTD)

3007573469-2015-00178 (Corp)

Model: FG Accessories (Product code: 36970)

Event Description: It was reported that a ResMed DC/DC Converter caught fire. There was no patient injury reported as a result of this incident.

Date of Awareness: 4 May 2015

ResMed’s Investigation: An engineering investigation was performed on the returned power converter by the design facility. Investigation identified that most likely root cause of the reported incident was a faulty electrical component. Based on all available evidence, the component was damaged by mechanical stress.

ResMed's risk analysis for this failure mode concludes that the risk is acceptable.

There was no patient injury reported for this incident.

Overall rate of issue at the time of investigation is 0.00160% (based on 62610 units sold).

2. Report Number: 3004604967-2016-00416 (LTD)

3007573469-2016-00416 (CORP)

Model: Power Station II (Product code: 24925)

Event Description: It was reported to ResMed Japan that a ResMed Power Station failed to charge properly while being used with an Astral device. There was no patient injury reported as a result of this incident.

Date of Awareness: 24 March 2016

ResMed’s Investigation: The device was returned for investigation and the reported complaint could not be confirmed.

Investigation tests did not reveal any anomaly on the returned RPS II. Several charge tests were performed


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and for each charge cycle, the RPSII charged correctly for less than 4 hours.

Based on the acceptable risk to the patient and remote occurrence rate, this complaint investigation was closed with no further actions required.

Overall rate of issue at the time of investigation is 6.889% (based on 7,156 units sold).

3. Report Number: R1600171

Model: FG Tubing (Product code: 14994)

Event Description: It was reported to ResMed that tubing was torn causing an error message on the connected device. No injury or adverse event was reported.

Date of Awareness: 20 April 2016

ResMed’s Investigation: The incident was directly reported to the regulators by the customer. A similar investigation determined that the root cause is a manufacturing defect however, due to the low occurrence rate, the complaint was closed with no further action. ResMed's risk analysis for this failure mode concludes that the risk is acceptable.ResMed's risk analysis for this failure mode concludes that the risk is acceptable.

1. Report Number: R160920

Model: FG Tubing (Product code: 14994)

Event Description: It was reported to ResMed that tubing was torn causing an error message on the connected device. No injury or adverse event was reported.

Date of Awareness: 20 July 2016

ResMed’s Investigation: The incident was directly reported to the regulators by the customer. A similar investigation determined that the root cause is a manufacturing defect however, due to the low occurrence rate, the complaint was closed with no further action. ResMed's risk analysis for this failure mode concludes that the risk is acceptable.

2. Report Number: 3004604967-2017-01079

3007573469-2017-01079


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Model: Air 10 Accessories (Product code: 37344)

Event Description: It was reported to ResMed that the power source unit (PSU) allegedly caught fire and caused a power outage.

There was no patient injury reported as a result of this incident.

Date of Awareness: 3 July 2017

ResMed’s Investigation: ResMed has requested for the device to be returned so that an engineering investigation could be performed. The device was reported to have been discarded by the user, therefore ResMed is unable to confirm the alleged malfunction at this time. Based on the actual field occurrence and severity of the reported fault, the risk is unchanged and remains acceptable.

3. Report Number: 3004604967-2017-01598

3007573469-2017-01597


Event Description: It was reported to ResMed that an Astral external battery failed to charge.


Date of Awareness: 16 Oct 2017

ResMed’s Investigation: The Astral external battery was not returned to ResMed for an investigation.

Based on all available evidence and complaint investigations of a similar nature, the investigation determined that the root cause was an isolated component failure within the battery assembly.

ResMed concludes that the risk associate with the use of the device is acceptable.

4. Report Number: PR1527328


Event Description: It was reported to ResMed that a patient using a Stellar device passed away. The power cable connecting the RPS II external battery and the device was found to be damaged as the device was not able to detect the external battery when the cable was bent.

Date of Awareness: 21 June 2018


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ResMed’s Investigation: The evaluation identified that based on available information, it does not appear that the device performance had contributed to the patient’s hospital admission and subsequent death event, as the device was performing to specification and had activated alarms appropriately. In this case, it is likely that the device had shut down as the internal battery has been fully discharged and the disconnection of the external battery may have been unnoticed by the patient/carer.

5. Report Number: 3004604967-2018-01542

3007573469-2018-01541


Event Description: It was reported to ResMed that an Astral external battery failed to charge.


Date of Awareness: 27 September 2018

ResMed’s Investigation: The device was returned to ResMed and an evaluation confirmed the complaint. The power station was scrapped per customer's instructions as the unit was damaged beyond repair.

ResMed's risk analysis for this failure mode concludes that the risk is acceptable.

All death and injury reports were assessed and investigated as per ResMed’s complaint handling and investigation procedures. These adverse events were found to be not related to the devices/accessories or bilevel therapy (discussed further in section 4.3.2.4).

Malfunction reports were also assessed and investigated and corrective and preventative actions were undertaken to rectify identified issues. These will also be discussed further in section 4.3.2.4.

4.3.2.3 Literature search and evaluation reports for PMS

The following section outlines reports of PAP-related adverse device reactions in the literature. A systematic literature review on the state-of-the-art of PAP therapy and OSA was undertaken on 19 Feb 2019 resulting in a total of 34 articles comprising Cochrane reviews, systematic reviews, meta-analyses, practice guidelines and narrative reviews. The literature plan, report, appraisal and analysis are reported in a standalone document internal ref. 21.

Common side effects reported with PAP therapy use include pressure on the face, mask discomfort, air leak, dry upper airways, skin breakdown, nasal congestion, aerophagia and pressure intolerance (35, 41). Most side effects associated with PAP therapy can be corrected by interventions such as proper


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pressure titration, efficient mask fitting and the use of humidification (34, 35). In paediatric patients, the use of PAP is generally associated with few side effects, which are similar to those observed in adult patients (25).

The following table is an extract from the supplementary material of the AASM task force paper by Patil et al. (34) listing possible PAP-related side effects:

Interface

Mask leak

Skin abrasion/ulceration (pain)

Mask allergy

Conjuntivitis/Sore eyes

Dermatitis/facial irritation

Claustrophobia

Pressure-Related (Airway)

Rhinitis

Rhinorrhoea

Sneezing

Desiccation

Sinusitis

Headache

Epistaxis

Otitis/Ear pain

Air swallowing/aspiration

Belching

Equipment-Related

Noise

Smell

Tubing condensation

Cumbersome equipment

Spousal intolerance/less intimacy

Ramp overuse

Equipment maintenance and cleaning

Equipment Failure

Lifespan of machine, tubing and mask

Recurrence of OSA

Pressure-Related

Mouth leak (dry mouth) or mask leak

Pressure intolerance

Sense of suffocation or difficulty exhaling

Tinnitus

Aerophagia

Pneumoencephalus

Central sleep apnoea

Prolonged oxyhemoglobin desaturations

General

Periodic limb movements

Anxiety

Insomnia

Headache

Fatigue/Feeling tired

Chest discomfort

While bothersome side effects can adversely affect treatment adherence, the consensus from the literature is that the side effects associated with PAP do not pose a risk to the user internal ref. 21.

Contraindications for PAP therapy are rarely discussed or investigated in the literature; they are established based on sound medical assumptions.

4.3.2.4 Complaints regarding performance and safety sent to the manufacturer, including the manufacturer’s own evaluation and report

All reported complaints are captured in ResMed’s complaints management system. The complaints are stratified into different categories according to the severity and patient outcome of the complaints. Complaints which involve serious adverse events or serious incidents such as death or injury, fire/flame or mislabel are captured as Category 1 complaints, while complaints which involve allegations of actual or potential malfunction of the device with no adverse events/incidents reported are captured as Category 2, which are not discussed in this section due to lack of clinical relevance. All reported complaints are assessed, evaluated and escalated as per ResMed’s complaints handling procedures.


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All reported complaints are investigated within defined procedures. The device investigation procedures involve thorough evaluation of the device and may include visual inspection of the condition of the entire device, system testing, software evaluation and a review of the patient therapy logs, where appropriate and possible. Summary of all investigation outcomes is provided and discussed later in this section.

A total of 24,478 complaints were reported to ResMed during this period [Nov 2014 - Nov 2018] for the present range of bilevel (AirCurve) devices. Of which, 38 complaints were categorised as Category 1, which consisted of death (2), injury (16), fire/flame (17), mislabel (3). Six complaints were in the others/malfunction category 2 (see Figure 11).

Figure 11. Cat 1 and Cat 2 Complaints for AirCurve 10 devices

A total of 65,461 complaints were reported for bilevel accessories in the same period of time. Of which, 45 complaints were categorised as Category 1, which consisted of injury (4), fire/flame (25), skin breakdown (1), mislabel (10), and non-injury (5). 51 complaints were in the others/malfunction Category 2.

The power supply unit drove the highest volume of complaints for bilevel accessories (16 total cases) with reports of burns, melting, and overheating issues, followed by the ClimateLine tubing (15) for similar issues, RPSII (5), DC/DC Converter (4) and SlimLine tubing (3) (see Figure 12).


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Figure 12. Breakdown of complaints for AirCurve accessories

Device Accessories

Total complaints 24478 65461*

Category 1

Death 2 0

Injury 16 4

Fire/Flame 17 25

Mislabel 3 10

Non-injury 0 5

Skin breakdown 0 1

Total 38 45

Category 2

Malfunction 6 51

Table 1: Summary of Category 1 and 2 complaints for bilevel device and accessories

*(Note: Not a true amount of complaints for bilevel accessories specifically – The number of complaints for accessories is higher compared to device, as the AirCurve devices share the same base unit as AirSense 10 class of products, hence the AirCurve and AirSense platforms will share identical groups of accessories. Therefore, the total number reflects complaints for all AirSense 10 and AirCurve accessories within the search period of Nov 2014 – Nov 2018.

(ResMed submits vigilance reports when these complaints meet the regulatory reporting requirements for all countries for which ResMed has regulatory approval. The number of complaints received may not reflect the number of vigilance reports submitted as discussed in section 4.3.2.2.2 as some complaints may deemed not reportable upon assessments.)


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The investigation based on complaints data concluded that the present range of bilevel devices did not cause or contribute to any serious adverse events since product launch in November 2014. Reports made to ResMed and device evaluations confirmed that no permanent impairments of body structure or body function as a result of a bilevel device / accessory malfunction.

Complaints data for device and accessories will be discussed in the following sections separately.

4.3.2.4.1 Death - Device

Two death incidents were reported to ResMed for patients being treated with bilevel device. The breakdown of death reports by country is shown in Figure 13. All death reports are evaluated and investigated by ResMed to determine device involvement. After evaluation and investigation of the available devices, it was found that both death incidents were deemed not related to the devices; no fault was found in the returned devices.

As stated in the user guide, the AirCurve devices are indicated for the treatment of OSA in patients weighing more than 13 or 30 kg (model dependant). Should a device malfunction and not deliver therapy, this will most likely only cause OSA symptoms such as gasping for air and/or snoring, and not result in any serious adverse event such as death.

Clinical expert comment: It is therefore important to note that death has not been identified as a new or increased risk for ResMed’s PAP devices. The risk management documentation does not identify death as a risk associated with the use of PAP devices for the treatment of OSA, which is consistent with the available state of the art and literature data, and is also consistent with the patient population for which the PAP devices are intended.

Figure 13. Breakdown of death reports (device)


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4.3.2.4.2 Adverse events other than death - Device

Injury

During the stated period [Nov 2014 - Nov 2018], 16 reports of injuries were recorded. This involves any temporary bodily impairment that may or may not require a medical intervention. As shown in Figure 14, desaturation and burn accounted for the two most common types of injuries reported to ResMed, with 3 cases each, followed by known side effects such as nosebleed (2), respiratory infections (2) and adverse events not related to PAP therapy such as cardiovascular symptoms (2), and hospitalisation incidents (2).

Figure 14. Type of injury reported (device)

All reports of adverse events are investigated and evaluated by ResMed to determine if the device had caused or contributed to the adverse event (Figure 15). It was found that none of the reported injuries were caused or contributed to by the intended performance of the device. There was one report of injury, which potentially may have been caused or contributed by unintended usage of the device. A patient had sustained a burn injury, which was caused by unintended body contact with the power supply unit for prolonged duration. It was reported by the patient that he/she was sleeping with the power supply unit under the blanket in bed.

There were 3 reports of desaturation incidents, all of which were deemed as not related to the device, as no faults were found with the returned devices and/or patients had deteriorated due to illness-related causes.

There were 3 reports of burn, one of which was caused by unintended body contact with the power supply unit for a prolonged duration (as mentioned above), and the remaining 2 burn reports could not be confirmed, as the devices were not returned for evaluation.

There were 2 reports of injuries categorised as known side effects of bilevel therapy, such as nosebleed. They are not usually a permanent occurrence or life threatening and can be minimised or prevented with optimal mask type/fit and humidification.


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There were 2 reports of chest and sinus infections, which were all deemed as not related to the device. Bilevel therapy and/or bilevel devices are not a known risk factor for respiratory infections.

There were also 2 reports of stroke incidents, both of which were assessed and found to be unrelated to bilevel therapy or bilevel device, as there are no known physiological links between stroke and bilevel therapy/device.

There were 2 reports of hospitalisation, one of which was for hypercapnia, and was deemed to be not related to the device, as there was no fault found with the returned device. Another report of hospitalisation was for an unspecified reason, and the device involvement in this incident could not be established as the device was not returned for evaluation.

2 other adverse events which were reported to ResMed including reports of seizures and lung problem (unspecified). They were assessed and deemed to be unrelated to bilevel therapy or bilevel PAP devices, as there are no known physiological links between these conditions and bilevel therapy/device.

Clinical expert comment: None of the reported injuries suggest new or increased risks for ResMed’s PAP devices.

Figure 15. Device involvement – injury (device)

Fire/Flame

A total of 17 reports of fire / flame-related events were recorded during the stated period [Nov 2014 - Nov 2018], which did not result in any patient injury. Based on problem descriptions, these events included fire, burn marks on device, overheating, melted units or power cords, burning smell, smoking and sparking. None of the 17 reports resulted in a sustained or life-threatening flame or fire situation.


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Clinical expert comment: The risk management documentation identifies this as a known risk that has been adequately mitigated and the analysis of the post-market data available has not identified any device-related issues requiring corrective action/s. The causes of the reported complaints did not relate to any patient safety issues that could be attributed to device-related faults.

Mislabel

Three reports of mislabelling events were reported. The majority of these reports were found to be related to errors in serial numbers, incorrect face plate or incorrect power plug. These have been assessed and deemed to pose negligible clinical risk to the patients. Clinical expert comment: The information contained in the state of the art section of this clinical evaluation report provides comprehensive information about the use of PAP devices for the treatment of OSA and identifies that the performance and safety of such PAP devices is well-established. Based on the analysis of the available manufacturer’s clinical data, including PMCF, as well as post-market data (as presented above), it is possible to conclude that the safety of ResMed’s PAP devices is acceptable. The information provided above is supportive of consistency between the state of the art, the available clinical data, the information materials supplied by ResMed, and the risk management documentation for the PAP devices.

4.3.2.4.3 Death - Accessories

There were no death incidents reported to ResMed in relation to usage of bilevel accessories.

4.3.2.4.4 Adverse events other than death - Accessories

Injury

During the stated period [Nov 2014- Nov 2018], 4 reports of injuries were recorded for bilevel accessories. This involves any temporary bodily impairment that may or may not require a medical intervention. As shown in Figure 16, the most common type of injury reported was burns, which accounted for about 50% of the injury reports (2 total cases) followed by chest pain and electric shock.

All reports of injuries are investigated and evaluated by ResMed to determine if the device/accessory had caused or contributed to the adverse event. It was found that none of the reported injuries were caused or contributed to by the intended performance of the device/accessory.


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Figure 16. Type of injury reported and device involvement (accessories)

Out of the 2 reports of burn injuries, 1 was reported for ClimateLine tubing and the other was reported for the power supply unit. Both reports were assessed and as the accessories were not returned for evaluation, these burn reports could not be confirmed, and based on the hardware and software mitigations in place in the device system, the ClimateLine tubing and power supply unit are not likely to cause burn injuries under intended operating conditions.

There was 1 report of chest pain when the power supply unit of the device did not appear to function. The device and the power supply unit were not returned for evaluation, hence the complaint could not be confirmed. However, in the event of a device malfunction and not being able to deliver therapy, this will most likely only cause OSA symptoms such as gasping for air and/or snoring, and not likely to cause chest pain.

There was 1 report of a patient being (electric) shocked by the ClimateLine tubing. The device and the tubing were not returned for evaluation. However, under intended operating condition, the design of the flow generator ensures that the main power supply is isolated from the tubing and mask assembly, and that the tubing and mask are safeguarded from any electrical hazards.

Fire/Flame

A total of 25 reports of fire / flame-related incidents were reported for bilevel accessories during the stated period [Nov 2014-Nov 2018], which did not result in any patient injury. 11 of these complaints were reported for power supply unit, 9 for ClimateLine Air tubings, 4 for DC-DC converter, and 1 for HumidAir tub. Based on complaint descriptions, these events included overheating and/or melting of power supply units, tubings or power cords. None of the 25 reports resulted in a sustained or life-threatening flame or fire situation.

Mislabel


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Ten reports of mislabelling events were reported for bilevel accessories such as the power supply unit (3), ClimateLine Air tubing (3), SlimLine tubing (3), and the oxygen connector port (1). Based on complaint descriptions, these reports were found to be related to incorrect power cords provided, missing labels, and incorrect packaging. The power supply units and oxygen connector ports were reported as out of box failures, and did not have any patient involvement. All reports have been assessed and deemed to pose negligible clinical risk to the patients.

Non-injury

There were 5 reports of charging issues for RPSII, which did not result in any adverse events, but were captured as Category 1 complaint, as these power stations were used with ResMed’s ventilators. Therefore, these reports will not be discussed here, as they are not related to bilevel device/ therapy.

Skin Breakdown

There was 1 report of burn injury to the face, as the patient was sleeping with the ClimateLine tubing on the face. The burn report could not be confirmed as the tubing was not returned for evaluation. Based on the hardware and software mitigations in place in the device system, the ClimateLine tubing is not likely to cause burn injuries under intended operating conditions.

Complaints (mainly Category 1 and 2) requiring further investigation by ResMed’s investigation team were escalated through the complaints handling system. The following table lists all the investigations conducted since product launch, the cause code assigned to the investigation and the problem code which best describes the symptoms experienced by the user. When any investigation revealed a root cause requiring correction action(s), a reference to the CAPA document is provided in the table. Summary of 9 investigations for AirCurve 10 devices:

No Investigation Product Cause Code Problem Code CAPA

(Document ID, Investigation ID and

Complaint Description)

1 eLB1098-0153 - PR1000069 -

REF53430 Smell, Electrical

AirCurve VAuto 10

Contamination Fire/Flame Nil

2 eLB1098-0240 - PR1375213 -

REF190686 Smell or Electrical - Machine smoking and melted

AirCurve 10 VAuto

Contamination Fire/Flame Nil

3 eLB1098-0188 - PR1145386 - Patient hospitalized due to failure of equipment

AirCurve 10 S Contamination Injury Nil


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4 eLB1098-0193 - PR1168179 - REF110852

Heating/Over Heating

AirCurve 10 S No Fault Found Fire/Flame Nil

5 eLB1098-0206 - PR1206725 -

Reported injury from device

AirCurve 10 VAuto

Not related to the device

Injury Nil

6 eLB1098-0214 - PR1244842 - Patient expired while using

AirCurve 10

AirCurve 10 VAuto

No Fault Found Death Nil

7 eLB1098-0226 - PR1309789 -

REF159753 Power cord got hot and

sparked with smoke

AirCurve 10 VAuto

Operator Error Melted Nil

8 eLB1098-0232 - PR1332908 - Smell, Patient had a stroke

AirCurve 10 ST No Fault Found Injury Nil

9 eLB1098-0267 - PR1602739 - Smoke

emitted

AirCurve 10 ST Water Damage Fire/Flame Nil

Based on all the investigations for AirCurve 10 devices, the table below summarises the cause code assigned to the outcome of the investigations:

Cause Code Quantity

Contamination 3

No Fault Found 3

Not related to the device 1

Operator Error 1

Water Damage 1

Contamination issue accounted for 33% of the complaints escalated for investigation. Another 33% of the investigated complaints revealed no faults with the devices, and the remaining were due to isolated issues such as operator error and water damage. As discussed earlier in section 4.3.2.2.1, actions and mitigation plans have been implemented to address these issues where necessary to improve the quality of the AirCurve 10 products.

4.3.2.5 Field Safety Corrective Actions

There were no field safety notices or corrective actions involving the devices under evaluation.


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4.3.3 Preclinical studies

The AirCurve 10 device range meets the predetermined performance criteria as defined in relevant compliance standards and system verification and usability protocols. Section 4.3.3.1 summarises compliance with performance and safety standards. Section 4.3.3.2 addresses the specific requirements of risk analysis and product specification and includes the requirements derived from regulatory standards. Section 4.3.3.3 provides an overview of the usability testing set out to confirm that the design of AirCurve 10 products is adequate and reduces the risk of use error. Ongoing performance standards are verified in bench model studies that replicate validated real-life patient parameters. The suite of patient model bench tests involving the devices under evaluation is described in section 4.3.3.4.

The table below summarises the outcomes of standardised reports that prove compliance with ISO 80601-2-70:2015 (section 4.3.3.1). System verification reports were undertaken for each device in the clinical evaluation addressing the specific requirements of risk analysis and product specification, and includes the requirements derived from regulatory standards (section 4.3.3.2) and therapy verification and validation from patient model bench tests (4.3.3.4).

Report Relevant device(s)

Outcome

ISO 80601-2-70:2015 Compliance report internal ref. 1

AirCurve 10 range

The devices comply with the applicable requirements contained in ISO 80601-2-70:2015.

TUV SUD test report on Newport ISO 80601-2-

70:2015 compliance internal ref.

26

AirCurve 10 range

The devices comply with the applicable requirements contained in ISO 80601-2-70:2015.

System V&V Summary Report (Newport) internal ref. 27

AirCurve 10 range

All system requirements passed the predetermined performance criteria.

Open Loop Testing – OSA Therapy Verification internal ref.

27

AirCurve 10 range

All Therapy Verification activities have been completed and all results concluded with a PASS.

Closed Loop Testing – OSA Therapy Validation internal ref.

27

AirCurve 10 range

All Therapy Validation activities have been completed and all results concluded with a PASS.

4.3.3.1 Standards compliance reports

The design of the AirCurve 10 device range has taken into account the internationally recognised performance standards ISO 80601-2-70:2015 for basic safety and essential performance of sleep apnoea breathing therapy equipment. Performance requirements identified in ISO 80601-2-70:2015 can be summarised as follows:

Sound pressure levels emitted by the device shall be measured in accordance with ISO 4871:1996 and ISO 3744:2010 and disclosed accordingly.

The stability in the delivery of static and dynamic airway pressure accuracy shall be verified for each therapy mode.

Maximum flowrate capabilities shall be formally tested and disclosed. A protection device preventing the airway pressure from exceeding the maximum limited

pressure of 30 cm H2O in normal conditions and of 40 cm H2O in single fault conditions shall be provided.


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Rebreathing of carbon dioxide shall be minimised to an acceptable level.

ResMed conducted internal tests showed that the AirCurve 10 range fulfils ISO 80601-2-70:2015 requirements internal ref. 1. Compliance was additionally confirmed in an external examination performed by the TUV SUD group (Test Report No. 7191156151-EEC17/HMH) on 27th Apr 2017 involving the AirCurve 10 devices internal ref. 26. Tests on the device systems were carried out with the integrated humidifier, standard 90W power supply unit, SlimLine air tubing and standard air tubing. Performance requirements were all met, as were requirements on equipment accessories, protection against hazards from equipment as well as device identification, marking and documents internal ref. 26.

4.3.3.2 System verification reports

Verification and validation tests for the devices under evaluation confirmed the products meet the predetermined acceptance criteria internal ref. 27. Individual system verification reports are dedicated to specific topics. The following section details test cases. Individual test protocols are kept on file at ResMed and test results are compiled in a separate document internal ref. 28.

4.3.3.2.1 Pressure performance

Pressure Accuracy and Jitter and Swings: This report tested that the flow generator is able to maintain pressure accuracy with acceptable pressure jitter in static scenarios and pressure swings in dynamic scenarios as per system requirements.

Blower Flow Performance: This report tested that the FG, under a normal and high load condition, can provide the minimum flow expected of the FG system.

Pressure Performance at Positive and Negative Flows: This report tested that the FG is able to maintain pressure accuracy at positive flows of up to 120L/min positive flows and negative flows of up to -30L/min at different atmospheric conditions.

Dynamic and Static Pressure Stability: This report tested the static and dynamic pressure stability of the FG and ensured that pressure is able to be maintained over the period.

Flow Measurement Accuracy: This report tested the accuracy of reported flow measured from the FG.

Dynamic and Static Leak Accuracy: This report tested the accuracy of reported leak measured by the FG and ensure that it is within tolerance.

Mask Diffuser Compensation: This report confirmed that the mask diffuser parameters on the FG are correct for each mask setting and according to specifications.

Patient Circuit Pressure Compensation: This report confirmed that the patient circuit hose drop parameters on the FG are correct for each mask, tube and humidifier setting and according to specifications.

Respiratory Flow Calculation: This report determined that the patient flow and dynamic leak parameters calculated by the FG are within specifications.

Patient Parameters Estimation: This report verified the accuracy of patient parameters; minute ventilation, tidal volume and respiratory rate, reported by the flow generator over the range specified.

4.3.3.2.2 Comfort Algorithm Parameters

Pressure Ramp in OSA Modes: This report confirmed that the device behaves correctly using Fixed Ramp functionality.


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Auto Ramp: This report confirmed that the FG behaves correctly in different Sleep Onset conditions using Auto Ramp functionality.

4.3.3.2.3 FG Interfaces and Comms

FG Comms Interface (Internal and External): This report verified the different functions that can be controlled on the device’s FG via the FG Comms (Serial) Interface without interrupting the therapy delivery.

Oximetry Module Connection and Errors: This report tested the FG connection to the oximetry module as well as the handling of errors and corresponding messages.

Oximetry Module Functionalities: This report verified the correct use of the oximetry module with the device’s flow generator in recording the oxygen saturation and patient heart rate and the compatibility of the oximetry module with the internal CAM and the Nonin XPod variants.

Software Upgrades: This report verified that the FG software shall be upgradable and that the process of upgrading the software will not affect therapy.

Internal Wireless Module (CAM) General Functionalities: This report verified the CAM is configured correctly, can handle specific errors and can establish a connection with a cellular network to transmit data from the device. The report also verified the display of parameters specific to the CAM on the FG.

Wireless Summary Data Transfer: This report verified that the summary data (Usage) is uploaded upon the occurrence of an OMO (On Mask-Off) event for all the modes supported and verify the integrity of the summary data being uploaded.

Wireless Settings Transfer: This report verified that the settings are applied or retrieved upon the occurrence of a trigger event for the CPAP mode supported by the device and the integrity of the settings being applied.

4.3.3.2.4 Therapy Functionalities

Snore Index of OSA: This report confirmed that the device is able to detect and report the level of snore under various conditions define in the specifications.

Response to Snore: This report confirmed that the FG response correctly based on the detected snore level with and without leak factors.

Apnoea and Hypopnoea Detection: This report confirmed that the FG detects Apnoeas and Hypopneas, and records their duration (apnoeas) under various pneumatic conditions.

Apnea Response: This report verified that the device provides expected pressure response to obstructive apnoeas over a define set of pressure settings and leak.

Flow Limitation (FFL) Response: This report verified that the device provides the expected pressure response upon detection of flow limited breath under various pressure settings and leak.

Closed Airway Discriminator (CAD) Detection: This report confirmed the FG accurately reports open, closed and unknown apnoeas, and scoring of AHI, AI, HI, OAI, CAI and UAI are accurate.

Prescription Limits and Decay for OSA Modes: This report verified that the limits of prescribed pressures due to events and the decay of the prescribed pressure when there are no events detected.

Trigger and Cycle for OSA Modes: This report verified that the device is able to trigger and cycle reliably as required of the system.


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Pressure Overshoot, Rise and Fall Time: This test verifies the pressure rise time, fall time and the overshoot functionality.

Therapy with Supplemental Oxygen: This report verified the various essential performance of the FG with addition flow of supplemental oxygen into the system.

4.3.3.2.5 Therapy Waveform Performance

Therapy Waveform Performance of Modes with EPR: This report confirmed that when that the pressure waveform of therapy with EPR delivered by the FG is as per design specifications.

4.3.3.2.6 Mechanical and Environmental Conditioning

Delivered Air Temperature at Mask: This report determined that the measured air temperature delivered to the patient's mask remains below the specified safe temperature limit under all normal operating conditions.

Enclosure Surface Temperature: This report determined that the enclosure surface of the device under test exceeds a certain temperature limit.

Pressure Performance at Varying Altitudes: This report tested the FG at various air pressures from 680hPa to 1060hPa and confirmed that the therapy is within specifications at those altitudes.

4.3.3.2.7 Data Integrity

SD Card Validation: This report tested the validation of an SD card with supported/unsupported formats, insertions, removals, and the presence of identification files.

SD Card Settings and Targeting: This report tested that settings can be applied to the FG via SD card and that it is possible to target particular users via pre-defined parameters.

SD Card Integrity and Corruption: This reported tested the validation of the data card when inserted into the FG and detection of a corruption of the card.

SD Card Data Recording and Writing: This report tested the conditions in which the SD Card therapy data can be stored and accessed. The file naming format, writing of SD card and testing of full capacity was also checked.

Summary Data Availability: This report tested that the Summary and Statistics Data is updated and available in accordance with minimum time and date requirements when a session is completed.

Statistics Summary Data: This report tested that the structure and content of the Summary and Statistics data reported from the device is in accordance with the FG Packet Data column for the respective product variant being tested.

Patient Compliance Mask Events Logging: This report verified that mask events are detected and recorded correctly at different conditions defined by the specifications.

4.3.3.2.8 Visual Inspection

Labelling on Guides/Manuals Inspection: This report verified that all labelling requirements are correctly incorporated into Information guide, Clinical guide and/or Welcome guide of the device.


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General User Interface Inspection: This report verified that general user interface on the device is as specified.

User Interactive Components and Indications: This report verified that all physical user interfaces are responding correctly for their intention.

Clock and Calendar Accuracy: This report tested the FG clock and calendar functionality and the accuracy of the clock.

Setting Rules and Collaterals: This report confirmed that the different sets of rules in Clinical Settings menu are met for different modes.

Clinical and Patient Settings Inspection: This report tested the various functions of the user interface.

Inspection of Humidifier Interface Operation: This report verified the cool-down operation of humidifier interface on the FG following termination of therapy or warm-up operation.

4.3.3.2.9 Safety and Mitigation

System Monitoring and Error Logging: This report tested the FG will go into error mode upon the detection of an overpressure or over-temperature condition.

Humidifier and Heated Tube Faults and Errors: This report tested the conditions and FG behaviour when humidifier or heated tube faults are generated.

4.3.3.2.10 Power Supply

Power Interruptions and Operation Transitions: This report tested the FG response after a power interruption and confirm the FG is still working correctly and that all required data is saved to a log file upon power-down.

4.3.3.2.11 Humidification

Humidification Performance: This report ensured the humidifier can maintain humidification over various flow rates according to system specifications.

Humidification Predicate Comparison: This report verified that the humidification performance of the HumidAir humidifier is substantially equivalent to, or better than, than its H5i humidifier used on ResMed’s previously released S9 series of PAP devices.

Heated Tube Performance: This report verified the performance of heated tubing at different environmental conditions.

Humidification Output Stability: This report measured humidification stability over eight hours. Heater Plate and Water Temperature: This report measured the maximum temperature of the

humidifier heater plate and the water in the tub.

4.3.3.3 Usability evaluation

The usability standards relevant to the product design of the present device range are IEC 60601-1-6:2010: General Requirements for basic safety and essential performance – usability, and IEC 62366:2007: Application of usability engineering to medical devices. Usability requirements were assessed in various usability evaluations aimed to ensure that the product design adequately reduces the risk of use error as far as possible and that the design is adequate for the intended users.


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All of ResMed's verification build and released devices adhere to the same specifications. Regression analyses review this and define testing to confirm each build standard meets the specification internal ref.

29-31. Therefore, clinical evidence from usability evaluations on previous build standards is applicable to the released product.

The results of the usability evaluations are reported separately for the AirCurve 10 range while under development in the Newport project internal ref. 32-44. Taken together, usability tests were structured around five key sections that asked users to perform a series of given tasks posed in the context of typical-use scenarios.

Assembly: – General ease of assembly – Locating the connection point for the Climate line – Correctly connecting the heated tube

User comprehension of On/Off and Start/Stop functions: – Confusion around device state

Humidifier: – Releasing the humidifier tub from the flow generator – Opening the tub lid – Ability to fill to indicated levels – Filling through snorkel – Perceived ease of cleaning

Replacing components: – Locating the SD card port – Removing the SD card – Locating filter

The acceptance criteria for each usability test was that at least 80% of intended users can complete the required task without assistance/direction. Overall, the devices were found to pass the majority of objectives assessed with users finding the majority of tasks easy and intuitive. Some minor recommendations were made for the product designs going forward. The evaluations identified no areas where issues related to usability where risk to the health and safety of any users was increased. The outcomes for each respective usability evaluation are tabulated below.

User risk associated with usability were formally captured through a Usability Failure Modes and Effects Analysis (FMEA). The Usability FMEA analysed the design for potential failure modes and effects, and considered the recommended actions/mitigations that are proposed to reduce the risk to an acceptable level internal ref. 45. No unacceptable risks (failure modes without reasonable recommended actions/mitigations) were identified in proceeding with the intended design.

Document reference

Test case Outcome

Internal ref. 32

User interface

Overall, all usability items passed the objectives of intuitiveness and ease of use. Majority of users positively commented on the simplicity of the menus, particularly the home screen. The main usability issue revolved around confusion between the start/stop and on/off buttons. No errors were observed which could result in hazardous situations.

Internal ref. 33

Humidifier tub

The humidifier tub design passed all objectives in ease of use and intuitiveness. Improvements could be performed in the areas of around removing tub from humidifier, filling tub to Max line, replacing the tub to


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humidifier and ease of cleaning and drying the tub. The evaluation identified no areas where issues related to usability where risk to the health and safety of any users was increased.

Internal ref. 34

Humidifier tub with tubing

Overall, the humidifier tub design passed all objectives in ease of task performance, ease of use and intuitiveness. Some improvements should be considered in the area of intuitiveness in removal of the humidifier tub from the CPAP. The intuitiveness of the correct connection of the tubing the CPAP failed during this evaluation. Improvements in relation to this issue should be considered, primarily via the addition of visual and/or physical cues which limit any ambiguity in the understanding of this task. No errors were observed which could result in hazardous situations.

Internal ref. 35

User interface: Clinicians

The majority of users positively commented on the simplicity and usefulness of the menus. Some comments were made regarding the positioning of particular items in the clinician menu and the overall menu ordering. No errors were observed which could result in hazardous situations.

Internal ref. 36

Tubing connection

Each tubing connection system tested passed all objectives surrounding ease and intuitiveness of attachment and detachment of the tubing to/from the PAP device. A strong preference towards tubing connection concepts with swivel functionality were noted during the evaluation. No errors were observed which could result in hazardous situations.

Internal ref. 37

Humidifier tub

This tub version 3 design passed all objectives in ease of task performance, ease of use and intuitiveness. Improvements should be considered in the area of intuitiveness in removal of the humidifier tub from the CPAP. No errors were observed which could result in hazardous situations.

Internal ref. 38

Humidifier tub

The humidifier tub assessed passed all objectives in relation to ease of task performance, overall ease of use and intuitiveness. Improvements should be considered, particularly in regards to the intuitiveness of removing the humidifier tub from a device. No errors were observed which could result in hazardous situations.

Internal ref. 39

Device system

evaluation

Overall this evaluation has shown that The Newport PAP System passed all objectives assessed with regards to ease and intuitiveness of task performance. A recommendation has been made regarding packing of the PAP system into the bag. No observations of user errors or hazardous situations were made.

Internal ref. 40

Tubing evaluation

The tubing design tested passed all objectives in ease of task performance, ease of use and intuitiveness. No observations of user errors or hazardous situations were made.

Internal ref. 41

System usability: Patients

The Newport PAP System passed the majority of objectives. Three observations of user errors were made in relation to the interactions with the humidifier tub: Tub filling, emptying and cleaning. In addition, the system failed to be sufficiently intuitive with regards to locating the SD card slot on the device, inserting the SD card into the device, connecting


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the tubing to the device, understanding of the home button on the device, locating the device humidification settings, understanding indications from the user interface that tubing was being heated and understanding indications from the user interface that pap therapy had stopped. However, the risk of a hazardous situation arising from these use errors was deemed low.

Internal ref. 42

System usability: Clinicians

The Newport PAP System passed the majority of objectives assessed, including all objectives relating to ease of task performance. It was noted, however, that the system could improve intuitiveness of connecting tubing to the Newport device, intuitiveness of accessing the clinical menu and location of information regarding relative humidity percentage of climate control. No observations of user errors or hazardous situations were made during the system usability evaluation.

Internal ref. 43

Humidifier tub and SD

card

All objectives were passed with regards to investigations into humidifier tub and SD Card use. One minor use error involving the detachment of the SD card cover. No observations of user errors or hazardous situations were made.

Internal ref. 44

Overall usability

The Newport system passed all objectives assessed. The system performed well in most areas pertaining to the ability or intuitiveness of performing specific tasks for participants. Two minor areas where participants experienced greater challenges included home button function recognition, wireless signal strength icon recognition, recognition of therapy stoppage from user interface and tubing temperature icon recognition. This evaluation identified no areas where issues related to usability where risk to the health and safety of any users was increased.


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4.3.3.4 Patient model bench testing

ResMed carries out a wide range of bench testing to assess the performance of all aspects of therapy. The purpose of this section is to describe the different types of patient model bench testing and report the individual tests undertaken with the devices of concern. Test cases are listed within each category of bench testing. Individual test protocols are kept on file at ResMed and test results are compiled together for the present range of AirCurve 10 devices internal ref. 46.

4.3.3.4.1 General Therapy Performance

This includes system performance aspects related to air pressure delivery and measurement. A subset of this test suite is required for harmonised standards compliance. General system verification tests such as pressure accuracy, pressure stability, blower flow performance, flowrate capabilities and static and dynamic airway pressure delivery are outlined in sections 4.3.3.1 and 4.3.3.2.

4.3.3.4.2 Therapy Functions Verification

Therapy Functions Verification, also referred to as open loop testing, ensures that individual aspects of therapy algorithms perform as intended and to a non-inferior performance level as its predicates. Protocols use predetermined sequences of breaths to drive the piston of a breathing machine in order to simulate patient breathing (either computer-generated breaths or breaths from clinical trials). For instance, flow limitation open loop testing utilises a broad range of flow limitation shapes to maximise the coverage of shapes, which could occur in clinical practice. These tests are performed under various conditions (e.g. mask leak) and settings. The device’s responses are assessed according to pass/fail criteria.

A list of test cases is given below. Individual test protocols are kept on file at ResMed and test results are compiled separately for AirCurve 10 devices.

Therapy Algorithms

– Apnoea response (only VAuto) – Flow limitation response (only VAuto) – Snore response (only VAuto) – Algorithm response and decay within limits (only VAuto)

Reporting

– Closed airway detection – Apnoea and hypopnoea detection

Others

– Pressure Support waveform performance – Therapy with supplemental oxygen

4.3.3.4.3 Therapy Validation

Therapy Validation, also referred to as closed loop testing, ensures that all therapy functions provide adequate therapy under realistic conditions. Methods include high-fidelity, highly integrated computational models of patient physiology, i.e. a virtual patient model. The device reacts to the virtual


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patient’s breathing and the virtual patient reacts to the device’s responses, essentially creating a feedback loop.

Included are as many physiological sub-systems as needed to recreate the essential respiratory characteristics of the target pathology. The structure integrates the upper airway, respiratory system resistance and compliance, respiratory muscle performance, gas exchange, heart and circulation, control of breathing, sleep and arousal. This standard structure is capable of achieving different respiratory characteristics, depending on the tuning of key parameters.

The patient models thereby replicate a predetermined target physiology with intra-patient and inter-patient variability. The high-level characteristics for each patient type that are predefined or 'scripted' include the patient’s condition (pathology, age, upper airway vulnerability) and the patient’s target sleep structure, but everything that happens during therapy including both the patient's and device's response is entirely unscripted. This method of preclinical patient model bench testing of a closed loop breathing circuit conforms to the state-of-the-art (68).

When compared to a real patient scenario, these models offer the crucial advantage of a stable and repeatable pathological condition and target sleep structure. Efficacious therapy may allow the patient to achieve the target sleep structure and respiratory outcomes, whereas suboptimal therapy will invoke for instance respiratory disturbances, arousals and poor blood gas exchange. Therapy efficacy can be ultimately assessed using clinically relevant model metrics such as patient flow, patient effort, oxygen desaturation and AHI.

Therapy Validation was carried out for the AirCurve 10 series. The virtual patient model was set to simulate a variety of events characteristic of real-life OSA patients (obstructive apnoeas and flow limitations). The devices were tested under various conditions such as different pressure support and different mask leak. The device’s responses were electronically recorded as well as manually scored by a clinical representative. AirCurve 10 series passed all objectives of the Therapy Validation tests and AHI was reduced to below 5 internal ref. 46.


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4.4 Clinical data from the literature

The aim of the review was to identify literature involving the devices under evaluation and analysing how they support or challenge the devices on the market. The literature plan, report, appraisal and analysis are reported in a standalone document internal ref. 47.

The literature search process used by ResMed is detailed in the Quality Management System template internal ref. 22 compliant to the requirements identified in 2.2. ResMed adopts best practise procedures to ensure data integrity during the literature search process. A second qualified person performed and reviewed the literature search.

The device-specific literature search was undertaken on 21/11/18 in PubMed, Embase, Cochrane Library and Google Scholar using the names of the devices, relevant therapy modes and variations. No time range was set for the search since it was the first device-specific literature review on the AirCurve 10 range of bilevel PAP devices. The following screening criteria were applied to search results:

Inclusion screening criteria: o Literature must involve one of the devices of concern. o Literature must be in keeping with the intended use and intended population.

Exclusion screening criteria: o Literature not analysing any of the devices of concern directly

Publication may be forwarded to the state-of-the-art literature review where relevant.

o Non-peer-reviewed literature (e.g. white paper, conference abstract) or a result from a different scientific field.

o Literature reporting outcomes on the devices of concern outside the intended use and intended population will be excluded. Published uses of the devices of concern outside the intended application or

population may be forwarded to a separate analysis on off-label use. o Study protocols or ongoing clinical trials (applicable to Cochrane Library and Google

Scholar) o Patents or citations (applicable to Google Scholar only) o Duplication of search results

Across all four databases, a total of 88 hits were found. Of these, 83 were excluded with the most common reason for exclusion pertaining to “Non-peer-reviewed literature (e.g. white paper, conference abstract) or a result from a different scientific field”. 70 of the 83 exclusions occurred during the search in Google Scholar not least due to being the last database searched and some duplications of results occurring, but also likely related to its wide coverage and hence identifying a proportionally greater volume of non-peer reviewed literature. In total, four results met the screening criteria. The outcomes of each individual search are detailed within the literature review document that includes a list of excluded and included articles with reason for exclusion, where applicable internal ref. 47. The outcomes of the appraisal are outlined in section 4.5.2 below.


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4.5 Appraisal of the clinical data

The objective of the following section is to summarise the outcome of the appraisal of the clinical data (as per criteria defined in the clinical evaluation plan internal ref. 4) for internal and external clinical data separately. The conclusion of the appraisal (4.5.3) draws on all sources of data together.

Since ResMed has deemed that the demonstration of conformity with General Safety and Performance Requirements based on clinical data is not necessary for the present range of bilevel PAP devices, evidence must be put forward that verify performance standards. As such, all devices must necessarily pass the predetermined acceptance criteria of system verification tests and prove compliance with the requirements of internationally recognised harmonised standards including ISO 80601-2-70:2015: Sleep apnoea breathing therapy equipment.

The clinical evaluation will identify, appraise and analyse all available clinical data to validate the ongoing safety and performance of the devices on the market as per MDR Annex XIV §1. This includes any premarket clinical investigations, PMCF studies, postmarket reports and usability evaluations undertaken by ResMed as well as clinical data from the literature involving the devices under evaluation.

Clinical experience data, such as PMS reports, will be appraised on whether or not it contains sufficient information (yes / no) for the evaluators to be able to undertake a rational and objective evaluation of the information and make a conclusion about its significance with respect to the performance and safety of the device in question.

All data derived from clinical investigations will be appraised in accordance with criteria specified in European guidance MEDDEV 2.7.1 Rev. 4.

Determining the methodological quality and the scientific validity involves ranking each data set on a three-point scale for the following categories: study design, sample, statistical measures, follow-up, report quality and compliance (with standards, plans and ethics). Based on the combination of scores, a data set may be classified as High, Medium or Low quality.

Clinical investigations will then be categorised based on whether the data are intended to directly demonstrate adequate clinical performance and clinical safety of the device (pivotal data), or whether the data serves an indirect supportive role (other data). To qualify as pivotal data, a data set must involve the same or equivalent device, be generated from an appropriate patient group, with outcome measures reflecting the intended performance of the device and emanate from a high quality report (MEDDEV 2.7.1 Rev. 4, section 9.3.2).

Assessing the strength of the contribution of each data subset to the overall clinical evaluation draws on outcomes from the quality and relevance appraisals in terms of source type and quality level in addition to evidence level, clinical significance and generalizability to the device family. The full appraisal plan is outlined in the clinical evaluation plan internal ref. 4.

Many of the internal clinical activities to support ResMed’s bilevel PAP devices were conducted outside the European Union with much of the data derived from an Australian OSA population. Similarly, studies identified in the literature review involving the devices of concern recruited from a variety of countries that also span EU countries. However, the patient populations in Australia and the EU with OSA can be considered similar.

Upper airway obstruction is caused by a partial or complete obstruction of the airway. Anatomical and physiological factors that can cause an obstruction naturally differ between individuals and geographical populations (69). Regardless, PAP therapy does not distinguish between types of obstruction. The therapeutic air pressure merely needs to be sufficiently high based on the severity of obstruction to establish a pneumatic airway splint.


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Variability in anatomy and physiology also does not impact the effectiveness of the VAuto algorithm. The VAuto therapy mode constantly monitors the state of the patient’s upper airway through feedback from pressure and flow sensors and respond to flow limitation, snore and apnoeas. This is independent of the underlying factors of the patient and therefore also of nationality or ethnicity.

In addition, a 2003 meta-analysis reported that the subjective and objective effects of PAP therapy were found to be homogenous across a diverse range of populations (country, gender, BMI and OSA severity) (63).

Taken together, the clinical data presented in this evaluation are deemed transferable to the European population.

4.5.1 Clinical data generated and held by ResMed

The following section appraises all available data generated and held by ResMed using the appraisal criteria defined in the clinical evaluation plan internal ref. 4. The individual studies are identified and described in more detail throughout section 4.3.

4.5.1.1 Clinical investigations generated and held by ResMed

The outcomes of the appraisal of clinical investigations generated and held by ResMed are summarised below:

QUALITY RELEVANCE CONTRIBUTION

Data set Device used

Score Outcome Score Outcome Score Outcome Input

Usability evaluations internal ref. 32-44

AirCurve 10 range

T2, N2, S2, F3,

W2, C1

Medium D1, A1, P1, O2,

R1

Other data

Y2, Q2, E2, M2,

G2 Limited Usability

PMCF study (Malhotra et al.

(17))

AirCurve 10 range

See section 4.5.2 for appraisal of published literature.

PMCF study (Woehrle et al.

(18))

AirCurve 10 range


PMCF study (Pepin et al. (65))

AirCurve 10 range


PMCF study (Benjafield et al.

(66))

AirCurve 10 S and AirCurve 10 VAuto

T1, N1, S2, F2,

W2, C1

High D1, A1, P1, O1,

R1

Pivotal data

Y2, Q1, E2, M1,

G1 Strong

Benefits; pivotal

performance

PMCF study (Cistulli et al. (67))

AirCurve 10 range

T2, N1, S2, F2,

W2, C1

Medium D1, A1, P1, O1,

R1

Pivotal data

Y1, Q2, E2, M1,

G1 Strong

Benefits; pivotal

performance Table footnotes: T1, T2, T3 = high, adequate, limited study design; N1, N2, N3 = Large representative, small representative, inadequate sample; S1, S2, S3 = high quality, adequate, limited statistical methods; F1, F2, F3 = rich and long, rich or long, limited follow-up; W1, W2, W3 = high quality, adequate, limited report quality; C1, C2, C3 = consistent compliance, minor deviation, major deviation; D1, D2, D3 = actual device, equivalent device, other device; A1, A2, A3 = same device use, minor


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deviation, major deviation; P1, P2, P3 = applicable, limited, different population; O1, O2 = yes/no outcome measure reflects intended performance; R1, R2, R3 = high quality report/data collection, minor deficiencies, insufficient information; Y1, Y2 = yes/no pivotal data; Q1, Q2, Q3 = high, medium, low quality level; E1, E2, E3 = evidence level hierarchy; M1, M2 yes/no clinical significance; G1, G2. G3 = applicable to whole device family, specific device, specific setting / mode of a device.

4.5.1.2 Clinical experience data

Data set Clinical

information in report

Period of report

Contribution to Sufficient

information in report

Trend reports (4.3.2.2.1)

Product Field Performance,

trending of issues and complaints

Product launch to Feb

2019 Performance Yes

Vigilance reports (4.3.2.2.2)

Any device malfunctions,

deterioration in device

performance, inadequate instructions, inadequate

labelling resulting in death, serious injury or serious deterioration in state of health.


2019

Safety / side effects

Yes

Complaints (4.3.2.4)

All adverse events and complaints

captured in ResMed’s complaints

management system.


2019

Safety / side effects

Yes

FSCA (4.3.2.5)

Report of any field safety corrective

action undertaken for a device under

evaluation.


2019 Safety Yes


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4.5.2 Clinical data from the literature

Clinical investigations from the literature were appraised using the same criteria for quality and validity, relevance and contribution as summarised above (4.5) and outlined in more detail in the clinical evaluation plan internal ref. 4.

The outcomes of the appraisal of clinical investigations derived from published literature are summarised below:

QUALITY RELEVANCE CONTRIBUTION

Data set Device used

Score Outcome Score Outcome Score Outcome Input

Ball et al. (21)

S7 VPAP Malibu

T1, N2, S2, F2, W1, C1


R1 Other data

Y2, Q1, E1, M1,

G3 Limited Other

performance

Malhotra et al. (17)

All devices from

AirCurve 10 and AirSense

10 range

T1, N1, S1, F1, W1, C1


R1 Pivotal data

Y2, Q1, E2, M1,

G1 Medium

Benefits; pivotal

performance

Woehrle et al. (18)

All devices from


10 range

T1, N1, S1, F1, W1, C1


R1 Pivotal data

Y2, Q1, E2, M1,

G1 Medium

Benefits; pivotal

performance

Pepin et al. (65)

All devices from


10 range

T1, N1, S1, F1, W1, C1


R1 Other data

Y2, Q1, E2, M1,

G1 Medium Benefits

Table footnotes: T1, T2, T3 = high, adequate, limited study design; N1, N2, N3 = Large representative, small representative, inadequate sample; S1, S2, S3 = high quality, adequate, limited statistical methods; F1, F2, F3 = rich and long, rich or long, limited follow-up; W1, W2, W3 = high quality, adequate, limited report quality; C1, C2, C3 = consistent compliance, minor deviation, major deviation; D1, D2, D3 = actual device, equivalent device, other device; A1, A2, A3 = same device use, minor deviation, major deviation; P1, P2, P3 = applicable, limited, different population; O1, O2 = yes/no outcome measure reflects intended performance; R1, R2, R3 = high quality report/data collection, minor deficiencies, insufficient information; Y1, Y2 = yes/no pivotal data; Q1, Q2, Q3 = high, medium, low quality level; E1, E2, E3 = evidence level hierarchy; M1, M2 yes/no clinical significance; G1, G2. G3 = applicable to whole device family, specific device, specific setting / mode of a device.

4.5.3 Conclusion of the appraisal of all clinical data

The following section offers a qualitative overview of the outcome from the appraisals of both sources of clinical data (internal and literature) with regards to amount, quality and contribution to the clinical evaluation.

Amount and range


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As per appraisal plan, evidence must be put forward that verify performance standards. This is appraised separately and is established with a pass in the respective validation and verification reports and standards compliance reports.

ResMed also carries out a wide range of bench testing to assess the performance of all aspects of therapy. Both the ‘open loop’ and ‘closed loop’ patient model bench tests comprise highly integrated computational models of patient physiology and may be categorised as pivotal premarket clinical investigations that are assessed on pass/fail basis.

Additional clinical investigations generated and held by ResMed included 13 usability evaluations as well as 5 PMCF studies with a cumulative total of over 2.5 million OSA patients. The literature review on the devices of concern yielded 1 additional data set (taking into account 3 items of internally generated published clinical data that appeared in the literature review).

With each report recording all events since product launch, the clinical experience data from PMS reports, complaints and FSCAs contains sufficient information to be able to undertake a rational and objective evaluation of the information and make a conclusion about its significance with respect to the performance and safety of the device in question.

PAP therapy is a well-established treatment option for OSA. Literature published since the release of the devices is thus more likely to capture recent advances in the field, such as telemonitoring tools, and less likely set out to establish safety and effectiveness directly. Nonetheless, 3 articles from the literature provide pivotal performance data from large OSA patient cohorts.

The range of outcomes tested by the clinical data sets is broad and includes pivotal performance data, other performance data, usability and clinical data on benefits. While no clinical investigations directly investigated safety or side effects of the devices of concern, none of the studies involving human participants identified complications from the use of the devices. Safety-related outcomes are corroborated by clinical experience data of the devices on the market.

Most of the data sets that were appraised involved all models from the AirCurve 10 range. Taken together with bench test reports and clinical experience data, the ongoing safety and performance is validated for each model in the clinical evaluation.

Quality and contribution

The methodological quality of the clinical evidence is good with all data sets assigned a quality level of either Medium or High. A certain standard of scientific rigour can be assumed from publications in peer-reviewed journals not least because all papers have undergone verified cycles of evaluation. Unpublished clinical investigations undertaken by ResMed such as clinical trials and usability evaluations follow Good Clinical Practice and harmonised standards including EN ISO 14155 as detailed in the Quality Management System template internal ref. 48.

In a single-session cross-sectional design, the usability evaluations provide input to patient-device interaction and determine whether the product design adequately reduces the risk of use error as far as possible and that the design is adequate for the intended users. However, contribution to establishing the safety and performance of the devices may be limited by lack of clinical significance.

Five high-quality non-randomised retrospective analyses featured similar study design and report quality but varying follow-up and sample sizes (17, 18, 65, 67). Together, these studies offer valuable treatment adherence and AHI data from a large number of OSA patients over 1 to 6 months in a real-world setting. All papers provided strong pivotal performance data (17, 18, 66, 67) with the exception of one, which was classified as contributing medium-strength non-pivotal benefit data (65).

One high-quality randomized trial involving a small representative sample provides additional performance data (21). The follow-up was short but rich following two overnight assessments in a sleep


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lab using the clinical sites’ polysomnography equipment. The contribution, however, is limited since the findings are transferable only to the VAuto therapy algorithm in the AirCurve 10 VAuto.

Overall conclusion

Considering that there are no requirements for exploratory or confirmatory investigations internal ref. 4, the number of internally-generated clinical investigations does not need to be assessed as adequate or not because the demonstration of conformity with the General Safety and Performance Requirements based on clinical data is not required.

The literature search yielded a modest amount of additional clinical data, which is consistent with the relatively recent release of the devices under evaluation. The overall value of the clinical data is substantiated by the level of quality of individual data sets, the range of outcomes tested as well as the wealth of clinical experience data for each model in the AirCurve 10 range of PAP devices.

Taken together, there is sufficient clinical evidence in amount and quality to facilitate a clinical evaluation.


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4.6 Analysis of the clinical data

As mentioned above, ResMed has determined that the demonstration of conformity with the General Safety and Performance Requirements based on clinical data is not required because PAP devices for OSA have a long history of safe use and are based on well-established technology and consistent claims with no significant innovative aspects.

All PAP devices work by simple physiological mechanisms that involve generating low pressures of air delivered through the nasal or oronasal passages that keep the airway open during sleep. The device-patient interaction is thus circumscribed to the resulting pneumatic splint along the pharyngeal airway.

Performance criteria and safety mitigations for PAP devices are clearly defined in harmonised standards for basic safety and essential performance of sleep apnoea breathing therapy equipment (ISO 80601-2-70:2015), which have been incorporated into the design of the AirCurve 10 range internal

ref. 1. As such, ResMed is able to demonstrate compliance with the General Safety and Performance Requirements by meeting the requirements of these internationally recognised standards without the need for additional clinical data.

Despite this, to validate the ongoing safety and performance of the PAP devices on the market as per MDR Annex XIV §1, ResMed has identified the relevant clinical data and the following subsections analyse these relevant clinical data. These clinical data include any premarket clinical investigations, PMCF studies, post-market reports, and usability studies undertaken by ResMed.

4.6.1 Requirement on safety

MDR’s 2017/745 General Safety and Performance Requirements #1, #2, #4, #5, #6, #10 and #23 state that:

(1) [Devices] shall be safe and effective and shall not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons, provided that any risks which may be associated with their use constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety, taking into account the generally acknowledged state of the art.

(2) The requirement in this Annex to reduce risks as far as possible means the reduction of risks as far as possible without adversely affecting the benefit-risk ratio.

(4) Risk control measures adopted by manufacturers for the design and manufacture of the devices shall conform to safety principles, taking account of the generally acknowledged state of the art […].

(5) In eliminating or reducing risks related to use error, the manufacturer shall (a) reduce as far as possible the risks related to the ergonomic features of the device and the environment in which the device is intended to be used […] and (b) give consideration to the technical knowledge, experience, education, training and use environment, where applicable, and the medical and physical conditions of intended users […].

(6) The characteristics and performance of a device shall not be adversely affected to such a degree that the health or safety of the patient or the user and, where applicable, of other persons are compromised during the lifetime of the device, as indicated by the manufacturer, when the device is subjected to the stresses which can occur during normal conditions of use and has been properly maintained in accordance with the manufacturer's instructions.


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(10) Devices shall be designed and manufactured in such a way as to [ensure safe and effective interaction between substances and materials of chemical, physical and/or biological nature and the human body].

(23) Label and instructions for use: Each device shall be accompanied by the information needed to identify the device and its manufacturer, and by any safety and performance information relevant to the user, or any other person, as appropriate.

ResMed makes no device-specific claims on the general safety of the devices of concern (see 2.7 for a full list of claims).

Based on the outcomes of the appraisal of the supporting clinical data, the conclusion for this analysis will be scored for quality, consistency, quantity and contribution as per table below (adapted for this purpose from internal ref. 49):

Strong Fair Limited

Quality - Scientific

rigor/validity - Considers design

and execution

Well-designed studies free from design flaws, bias

and execution problems.

Studies of strong design with minor

methodological concerns.

Studies of weak design or inconclusive findings due to design

flaws, bias or execution problems.

Consistency Of findings across studies

Findings generally consistent in

direction and size of effect with minor

exceptions at most.

Some inconsistencies among results of

studies.

Unexplained inconsistency among results from different

studies or single study unconfirmed by other

studies.

Quantity - Number of studies - Sample size

Several good quality studies;

Adequate sample sizes.

Limited number of studies;

Adequate sample sizes.

Limited number of studies;

Inadequate sample sizes.

Contribution To the research question

Pivotal data directly demonstrating

adequate clinical performance and

clinical safety of the device.

Outcomes relevant to research question but less immediate clinical

impact.

Outcomes less likely to affect benefit/risk

profile of device.

List of evidence to support requirements on safety:

Type of evidence

Document reference

Devices Relevant elements tested Outcome Applicable

GSPRs

Harmonised standards compliance

ISO 80601-2-70:2015 Compliance report internal ref.

1

AirCurve 10

Particular requirements for basic safety and essential performance of sleep apnoea breathing therapy equipment:

• Compliance with ISO 4871:1996 and ISO 3744:2010 on how to measure sound pressure levels

Pass (1), (4), (6), (23)


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Type of evidence

Document reference


GSPRs


TUV SUD test report on respiratory flow generator internal ref. 26

AirCurve 10

• Methods to test stable delivery of static and dynamic airway pressure accuracy for each therapy mode

• Methods to test maximum flowrate capabilities

• Not exceeding the maximum limited pressure

• Minimised rebreathing of CO2

Pass (1), (4), (6), (23)

System verification


AirCurve 10

To address the verification and validation activities which apply to the proper functioning of the device and its accessories (4.3.3.2).

Pass (1), (4), (6)

Risk analysis

Newport VPAP ST Risk Analysis Summary Report internal

ref. 23

AirCurve 10

To identify potential hazards associated with a device, estimate and evaluate the risks associated with these potential hazards, control potential risks, and continuously monitor the effectiveness of the controls.

The device has no Essential Performance features or functions and there are no combinations of settings that could result in a hazard with a Major effect severity. All other hazards were deemed negligible or tolerable with respects to benefits gained.

(1), (2), (4), (5), (6), (10), (23)

Hazardous materials

Volatiles and Particulates test (Newport) internal ref. 19-20

AirCurve 10

To report on the conduct and results of standard ResMed particulates and volatiles tests.

Specified materials are suitable for intended use, comply with ISO 10993-1 and have no negative effect on user.

(10)

Hazardous materials

Newport Materials Biocompatibility Reports internal ref. 50-55

AirCurve 10

Biocompatibility testing for cytotoxicity, sensitisation and extractables and leachables for materials (RoHS, Phthalates, BPA, Latex, Animal tissue, REACH and Nanoparticles) including those located in the respiratory pathway.

Majority passed. Nanoparticles present in some materials.

(10)

Labelling mitigations

Clinical appraisal of

AirCurve 10 Clinical appraisal of the labelling mitigations from our

All clinically relevant labelling mitigations

(23)


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Type of evidence

Document reference


GSPRs labelling in the user and clinical guides (Newport) internal ref. 56

risk analysis against the exact labelling in the user/clinical guides.

in the user and clinical guides for AirCurve 10 “bilevel sleep” devices have been appraised to be adequate, and changes have been proposed and implemented for those identified to be inadequate.

Usability evaluation

Usability evaluations internal ref. 32-44

AirCurve 10

To ensure that the product design adequately reduces the risk of use error as far as possible and that the design is adequate for the intended users.

The evaluations identified no areas where issues related to usability where risk to the health and safety of any users was increased.

(4), (5)

Usability evaluation

Usability FMEA (Newport)

internal ref. 45

AirCurve 10

To analyse the design for potential failure modes and effects, and considered the recommended actions/mitigations that are proposed to reduce the risk to an acceptable level.

No unacceptable risks (failure modes without reasonable recommended actions/mitigations) were identified in proceeding with the intended design.

(4), (5)

Clinical data from the literature

Bilevel Sleep device-specific literature review internal ref.

47

AirCurve 10

To plan, search, appraise and analyse published clinical data related to ResMed’s range of bilevel PAP devices for OSA.

No safety concerns emerged from the clinical data involving the devices of concern.

(1), (4), (6)

Clinical experience data


AirCurve 10

Analysis any device malfunctions, deterioration in device performance, inadequate instructions, inadequate labelling resulting in death, serious injury or serious deterioration in state of health.

A total of 3 vigilance reports were submitted since the launch of the devices on the market. No unexpected risks were identified.

(1), (5), (6), (10), (23)



AirCurve 10

Analysis of all reported complaints captured in ResMed’s complaints management system.

The investigation based on complaints data concluded that the devices under evaluation did not cause or contribute to any serious adverse events since product launch.

(1), (5), (6), (10), (23)


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Type of evidence

Document reference


GSPRs


FSCAs (4.3.2.5)

AirCurve 10

Report of any field safety corrective action undertaken for a device under evaluation since product launch.

There have been two no FSCAs involving an AirCurve 10 device.

(2)

Compliance with harmonised performance standards internal ref. 1 and 26 and system verification reports internal ref. 27 ensure that AirCurve 10 devices conform to established safety principles and function as intended and thus pose no unacceptable risk to the user and does not compromise clinical condition or safety of patients (GSPRs 1, 4, 6, 10 and 23).

A review of the risk analysis internal ref. 23, hazardous materials internal ref. 18, Fehler! Verweisquelle konnte nicht gefunden

werden.-55 as well as the platform labelling internal ref. 56 confirm that all the hazards have been identified appropriately and reduced as far as possible (GSPRs 1, 2, 4, 5, 6, 10 and 23). The AirCurve 10 device range has no Essential Performance; it is considered a low risk to the patient for the device to stop at any time during therapy, or to deliver air at a higher or lower pressure than prescribed, because of the underlying condition being treated (i.e. OSA). All other hazards were deemed negligible or tolerable. There is consistency between the user/clinical guides and the risk management documentation for the devices and the labelling instructions and mitigations are considered appropriate (GSPR 23).

Harmonised standards on usability (IEC 60601-1-6:2010 and IEC 62366:2007) were taken into consideration during the development of the devices under evaluation. Usability evaluations internal ref. 32-

44 further prove that the risk of use error has been reduced as far as possible (GSPR 4 and 5). The evaluation identifies no areas where issues related to usability pose unacceptable risk to the health and safety of device users.

PAP therapy for OSA has a long history of safe and effective use and is based on well-established technology and consistent claims with no significant innovative aspects. Clinical data from the literature involving the devices of concern were found to be in line with the general state-of-the-art for PAP therapy internal ref. 47. While none of the studies directly investigated safety-related outcomes, none of the studies involving human participants identified complications (GSPR 1 and 6).

An analysis of clinical experience data since the launch of the devices contained sufficient information to objectively verify years of safe and effective use of AirCurve 10 devices on the market (4.3.2.2) (GSPRs 1, 5, 6, 10 and 23). Two reports of death were found to be not related to the device of concern. Analyses of all complaints data found desaturation and burn accounting to be the two most common types of injuries reported to ResMed, with 3 cases each, followed by known side effects such as nosebleed (2) and adverse events not related to PAP therapy such as respiratory infections (2), cardiovascular symptoms (2) and hospitalisation incidents (2). Vigilance reports did not identify any unexpected risks (GSPRs 1, 5, 6, 10 and 23); from three vigilance reports, two cases showed that the device of concern was operating within specifications and in the remaining case, the device was not returned (4.3.2.2.2). There were no FSCAs involving the devices under evaluation (4.3.2.5) (GSPR 2).

Taken together, there is sufficient clinical evidence in amount and quality on all AirCurve 10 devices and their accessories for the detection of any safety concerns. AirCurve 10 devices are aligned to the same clinical applications and harmonised standards as used by hundreds of PAP devices with years of safe and effective use on the market. There is consistency between current knowledge / state of the art, available clinical data, user/clinical guides and the risk management documentation for the devices. No need for additional clinical data was identified.


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The safety of AirCurve 10 devices and their accessories is acceptable. Based on the outcomes of the appraisal of the supporting clinical data, the strength of the conclusion that safety requirements are fulfilled is as follows:

Quality: Strong Consistency: Strong Quantity: Strong Contribution: Strong


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4.6.2 Requirement on acceptable benefit-risk ratio

MDR’s 2017/745 General Safety and Performance Requirements #2, #3, #4, #8 and #10 state that:

(2) The requirement in this Annex to reduce risks as far as possible means the reduction of risks as far as possible without adversely affecting the benefit-risk ratio.

(3) Manufacturers shall establish, implement, document and maintain a risk management system. […]

(4) Risk control measures adopted by manufacturers for the design and manufacture of the devices shall conform to safety principles, taking account of the generally acknowledged state of the art […].

(8) All known and foreseeable risks, and any undesirable side-effects, shall be minimised and be acceptable when weighed against the evaluated benefits to the patient and/or user arising from the achieved performance of the device during normal conditions of use.

(10) Devices shall be designed and manufactured in such a way as to [ensure safe and effective interaction between substances and materials of chemical, physical and/or biological nature and the human body].

ResMed has evaluated the benefits to the patient against the potential risks identified for the use of the AirCurve 10 devices as detailed in the risk-benefit report internal ref. 25.

The assignment of benefit class was as follows:

Magnitude of Benefit

Significant Moderate Minor

Duration of Benefit

Long Benefit Class I Benefit Class I Benefit Class II

Substantial Benefit Class I Benefit Class II Benefit Class II

Short Benefit Class I Benefit Class II Benefit Class III

Benefit Class I : High level of benefit

Benefit Class II: Medium level of benefit

Benefit Class III: Low level of benefit

Detailed benefit classification:

Likelihood of benefit

High Medium Low

Benefit Classification

Benefit Class I

Benefit does not outweigh Risk

Class I UNACCEPTABLE





Benefit may outweigh Risk

Class II


Class II



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Class II UNACCEPTABLE

Benefit outweighs Risk Class III


Benefit outweighs Class III

Benefit outweighs Risk Class IV



Benefit Class II
















Class III Benefit outweighs

Risk Class IV Benefit outweighs


Risk Class IV

Benefit Class III














Class III


Class III


Class III Benefit outweighs



Risk Class IV


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The following table captures the generic benefits with the evidence supporting each individual benefit and the categorisations applied. Articles from the state-of-the-art literature review internal ref. 21 were used to record generic benefits specifically those articles identified as contributing to “PAP application / treatment guidelines” and “PAP safety and effectiveness”. Nine overview articles, critical reviews and systematic reviews specifically discuss benefits of PAP therapy and were thus found to be pertinent to the present analysis of generic benefits of PAP therapy.

Medical Conditi

on Article Sample Therapy Reported outcome

Magnitude of Benefit

Likelihood of Benefit

Duration of Benefit*


Benefit Definition

GRADE Level

REDUCED AHI

OSA Giles et al.

(14)

1,718 adult OSA patients (total

population, pooled analysis

of 36 trials)

CPAP

CPAP vs control: -26.49 events/hour (95%CI: -

35.64 to -17.34) versus -17.02 events/hour (95% CI: -19.25 to

-14.80)

Significant Medium Short Benefit Class I Patient index

High

OSA Patil et al.

(34) pooled analysis

of 11 RCTs CPAP

CPAP versus no therapy: -23 events/h

(95% CI: -29 to -18 events/h) Significant Medium Short Benefit Class I

Patient index

High

OSA Kushida et

al. (15) 2 clinical trials

Bilevel PAP

The AASM recommend that adult or paediatric patient may be switched to bilevel PAP if

CPAP is not effective or uncomfortable (Option).

Moderate Medium Substantial Benefit Class

I* Patient

reported Moderate

OSA Kushida et

al. (8) 2 clinical trials

Bilevel PAP

The AASM recommends bilevel PAP where high

pressure is needed and the patient experiences difficulty

exhaling against a fixed pressure or coexisting central

hypoventilation is present (Guideline).

Significant Medium Substantial Benefit Class I Patient index

High

OSA Kakkar & Berry (35)

N/A

CPAP and

bilevel PAP

Benefit of PAP therapy based on high levels of evidence

(multiple randomized controlled trials): Reduction in

the AHI

Significant High Substantial Benefit Class I Patient index

High


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OSA Mansukhani et al. (37)

2,602 OSA patients

(reference to 3 RCTs and 1 retrospective

analysis)

Bilevel PAP

Bilevel PAP was as effective as CPAP in reducing AHI as

measured over 1 to 30 months.


I* Patient index

High

IMPROVED OBJECTIVE SLEEPINESS

OSA Giles et al.

(14)

712 adult OSA patients (pooled

analysis of 3 parallel studies)

CPAP Avg. increase in Maintenance Wakefulness Test: 2.36 min

(95% CI: 0.31 to 4.40) Significant Medium Short Benefit Class I

Patient index

Moderate

OSA Beninati & Sanders

(16)

107 adult OSA patients

(reference to one RCT)

CPAP

Final mean Maintenance Wakefulness Test score for

active vs subtherapeutic CPAP: 32.9 vs 23.5 min

Significant Medium Short Benefit Class I Patient index

Moderate


N/A

CPAP and

bilevel PAP


(multiple randomized controlled trials): Improvement

in objective sleepiness

Significant Medium Substantial Benefit Class I Patient index

High

IMPROVED SUBJECTIVE SLEEPINESS

OSA Giles et al.

(14)



CPAP Avg. decrease in ESS: -3.83 units (95% CI: -4.57 to -3.09)

Significant High Short Benefit Class I Patient

reported High

OSA Patil et al.


of 38 RCTs CPAP

Avg. decrease in ESS: -2.4 units (95% CI: −2.8 to −1.9

points) Significant High Short Benefit Class I

Patient reported

High

OSA González Mangado et al. (38)



CPAP Sig. improvement in functional

outcome (subjective sleepiness and state of mind).

Significant High Short Benefit Class I Patient

reported Moderate

OSA Kushida et

al. (8) 10 RCTs CPAP

The AASM recommend CPAP for improving self-reported sleepiness in OSA patients

Significant High Substantial Benefit Class I Patient

reported High


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based on the highest degree of clinical certainty (Standard).


(16)



CPAP Final ESS score for active vs subtherapeutic CPAP: 7.0 vs

13.0 Moderate High Short Benefit Class II

Patient reported

Moderate

OSA Freedman

(36) Reference to 29

studies

CPAP and

bilevel PAP

All types of PAP therapy typically result in sig.

improvements in subjective sleepiness in adherent

patients with moderate-severe OSA.


reported High


N/A

CPAP and

bilevel PAP


(multiple randomized controlled trials): Improvement

in subjective sleepiness


reported High

OSA Mansukhani et al. (37)

2,602 OSA patients

(reference to 3 RCTs and 1 retrospective

analysis)

Bilevel PAP

Bilevel PAP was as effective as CPAP in improving ESS

scores as measured over 1 to 30 months.


I* Patient

reported High

IMPROVED QUALITY OF LIFE

OSA Giles et al.

(14)


analysis of 3 parallel and

partial crossover studies)

CPAP

Short-Form-36 outcomes showed avg. increase in

Physical Function score of 6.82 units (95% CI: 1.75 to 11.88) and General Health

score of 6.54 units (95% CI: 0.41 to 12.67).

Significant Medium Short Benefit Class I Patient

reported Moderate

OSA Patil et al.


of 8 RCTs CPAP

SAQLI outcomes demonstrated a clinically

significant SMD of 0.3 (95% CI: 0.1 to 0.5)


reported Moderate


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OSA Kushida et

al. (8) 7 clinical trials CPAP

The AASM recommend CPAP for improving quality of life in patients with OSA (Option).


I* Patient

reported High


(16)

Reference to 4 RCTs

CPAP Active CPAP associated with

sig. greater QoL scores vs control.


reported High


N/A

CPAP and

bilevel PAP

Benefit of PAP therapy based on lower levels of evidence

(uncontrolled studies, smaller number of studies, or

conflicting results): Improved quality of life (vitality) and improved nocturnal sleep

quality

Moderate Medium Short Benefit Class

I* Patient

reported Moderate

IMPROVED OXYGEN SATURATION

OSA Giles et al.

(14)



CPAP

Avg. increase in minimum oxygen saturation: 8.5 SaO2

(95%CI: -2.77 to 19.77); Avg. increase in daytime

oxygen saturation: 0.9 SaO2 (95% CI: 0.35 to 1.45)

Significant High Short Benefit Class I Physiologic

al parameter

High

OSA Mello-

Fujita et al. (28)

105 OSA patients with

stroke (reference to one

observational study)

CPAP Minimum oxygen saturation increased from 76+9.8% to 89±4.6% SaO2 after CPAP.


I*

Physiological

parameter Moderate

LOWER BLOOD PRESSURE

OSA Giles et al.

(14)



CPAP

Avg. decrease in 24-hour systolic BP: -7.24 mmHg (95%CI: -11.54 to -2.94); Avg. decrease in 24-hour diastolic BP: -3.07 mmHg (95% CI: -5.35 to -0.78)

Significant Medium Short Benefit Class I Physiologic

al parameter

Moderate


(Doc. #: D370-1459 Rev. 2.0)



*One doesn’t build up a tolerance to PAP therapy, so if PAP was used for a longer period of time and nothing changed in the patient’s condition, one would expect the same clinical benefit. Hence ‘short’ and ‘substantial’ durations of benefit noted in this column have the same weighting as ‘long’ durations of benefit.

OSA Patil et al.


of 26 RCTs CPAP

Pre vs post CPAP: Reduction of nighttime systolic SBP of −4.2 mmHg (95% CI:

−6.0 to −2.5 mmHg), and nighttime DBP of −2.3

mmHg (95% CI: −3.7 to −0.9 mmHg).

Significant Medium Short Benefit Class I Physiologic

al parameter

Moderate

OSA Kushida et

al. (8) 9 clinical trials CPAP

The AASM recommend CPAP for lowering blood pressure in

hypertensive patients with OSA (Option).


I*

Physiological

parameter High

OSA Freedman

(36) Reference of 4

studies CPAP

CPAP is associated with small but statistically sig.

improvements in diurnal mean arterial systolic and diastolic

BP (-1.8 to -3 mmHG).


I*

Physiological

parameter Moderate


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The benefits identified in the literature review involving the devices of concern internal ref. 47 are detailed in the table below:

*One doesn’t build up a tolerance to PAP therapy, so if PAP was used for a longer period of time and nothing changed in the patient’s condition, one would expect the same clinical benefit. Hence ‘short’ and ‘substantial’ durations of benefit noted in this column have the same weighting as ‘long’ durations of benefit.

Medical Conditi

on Article Sample

Device / therapy

Reported outcome Magnitude of Benefit

Likelihood of Benefit

Duration of Benefit*


Benefit Definition

GRADE Level

OSA Ball et al.

(21) 22 OSA patients VAuto

The auto-adjusting bilevel mode (VAuto) normalised AHI as

effectively as the standard bilevel mode (S).

Moderate Medium Short Benefit Class II Patient index Moderate

OSA Malhotra et al. (17)

128,037 OSA

patients

All AirCurve

10 devices

Patient engagement tool (myAir) plus telemonitoring (AirView) was

associated with sig. higher treatment adherence vs.

telemonitoring alone.

Low average AHI (<5) in both groups of PAP-treated patients.

Significant Medium Substantial Benefit Class I Patient index Moderate

OSA Woehrle et al. (18)

1,000 OSA patients

All AirCurve

10 devices

Additional patient engagement tool was associated with higher

treatment adherence compared to telemonitoring only.

Low average AHI (<5) in both groups of PAP-treated patients.

Significant Medium Short Benefit Class I Patient index Moderate


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ResMed assesses all hazards, effects and mitigations in order to identify potential hazards associated with the present device range, estimate and evaluate the risks associated with these potential hazards, control potential risks, and continuously monitor the effectiveness of the controls throughout the device’s life cycle. The risk analysis summary for AirCurve 10 devices internal ref. 23 states that the devices have no Essential Performance.

The Newport VPAP ST Risk Analysis Summary Report internal ref. 23 was used as the source of hazards leading to major-severity effects as it was put forward by Systems Engineering as the most recent risk analysis and represents all the Major Severity risks for ResMed bilevel sleep PAP units.

All hazards in the individual project risk analyses have been reduced as far as possible. The risk analyses were reviewed and all hazard risk levels are documented as being either Class III or Class IV (Quality Management System template on risk scales internal ref. 24):

All hazards in the project risk analysis for the devices under evaluation have been reduced as far as possible internal ref. 23. All hazard risk levels are documented as being either Level III or Level IV. All benefits identified either Class I thus outweighing Level III and IV risks as per benefit classification.

ResMed has assessed the benefits versus risk for all hazards; for convenience, an example of this is shown below for the Major-severity hazards in the table below. Note that layout consists of hazards followed by rows with related effects and affected populations.

Hazards Severity Severity

Class Mitigated

Likelihood

Mitigated

Risk Level

Benefit classification

Risk-Benefit Acceptability

H1 Excessive Pressure > 50cm H2O for > 1min



0.700000 Major Improbable III Benefit Class I Acceptable


Patients at increased risk of pneumothorax, pneumomediastinum or venous air embolism. (P25)


H9 Electrified Parts (>100 uA leakage current)


(Doc. #: D370-1459 Rev. 2.0)



Hazards Severity Severity

Class Mitigated

Likelihood

Mitigated

Risk Level

Benefit classification

Risk-Benefit Acceptability

Electrocution (death) (E12)



H12 Loose/particulate objects in airway

Asphyxia (E18)



H13 Smoke/fumes in Airway

Asphyxia (E18)



H14 Contaminated parts or air

Respiratory infection (e.g. pneumonia, aspergillosis) (E49)

Population that are susceptible to mould infection in the lungs (P29)


H17 Fire with supplemental oxygen

Asphyxia (E18)



Burns leading to serious injury or death (E24)



H18 Fire without supplemental oxygen

Burns leading to serious injury or death (E24)

Patient not using supplemental oxygen. (P26)


H20 Insufficient CO2 Venting

Asphyxia (E18)

Patients who arouse to hypoxia/hypercapnia due to rebreathing and are able to remove mask. (P17)

0.700000 Major Impossible IV Benefit Class I Acceptable

Please note that most Effects being reviewed have “Improbable” likelihood, however the ResMed risk analysis process mandates review of all Major severity class Effects regardless of likelihood.

The full content of the risk analysis is presented in the reference document internal ref. 25.


(Doc. #: D370-1459 Rev. 2.0)



A review of residual risks for compatible accessories confirms that the hazards are all considered in the table above.

ResMed is undertaking an analysis specifically on the materials used in the AirCurve 10 range, as summarised in the table below.

The conclusion of the analysis of the materials used in the products developed under the Newport project is as follows:

The materials analysis for AirCurve 10, collating data from suppliers, as per state of the art at the time of manufacture, and using analysis of materials in the air path has determined there are no identified substances of concern above 0.1% per weight of the AirCurve 10 flow generator.

What tested Document number Conclusion Newport

Newport: Nanoparticles

D005-006 Nanoparticles present in some materials. Nanoparticles include:

Titanium dioxide (TiO2) – pigment/modifier

Carbon black – pigment/colour agent Silicon dioxide (SiO2) – pigment/ pellet

dusting agent/ impurity found in calcium carbonate

Magnesium hydroxide (Mg(OH)2) Melamine cyanurate

Decabromodipheny (DBDPE) Antimony trioxide (Sb2O3)

Newport: RoHS Compliance

D370-1471 RoHS compliant.

Newport: RoHS, Phthalates and BPA Compliance

D370-1471 All materials used in wet and dry air paths:

- compliant with the RoHS and phthalates maximum allowable limit

-that contain BPA suitably identified as such in their respective DECs.

Newport materials: Suitability for use with respect to patient safety and risk of harm

D370-407 Specified materials are suitable for intended use in the Newport/S9 Shire/Juno S/ST & ST-A patient air path.

Meiban Micro Parts Patient and environmental risks caused

by the presence of Diazene-1,2-dicarboxamide (ADCA) in:

Meiban’s tubes, mask sub-assemblies and Air10 elbow

eLB0320-958 Patient safety risks have been assessed as Risk Level III. Risks rated Level III are tolerable risks if the effort involved in further risk reduction would exceed the improvement gained. Level III risks are subject to Review by management. Approval by management of this document constitutes acceptance of the identified safety risks.

SRX Global, Kaifa and Phihong Parts Patient and environmental risks caused

by the presence of substance of very high concern (SVHC):

In products including Newport products

eLB0320-1071 Risk Level deemed to be IV which is ‘Negligible Risk’

W&S Plastics Parts Patient and environmental risks caused

by the presence of Phenol, 2-(2H-benzotriazol-2-yl)-4,6-bis(1,1-

dimethylpropyl): In Newport flow plate and H5i chassis

eLB0320-1157 Risk Level deemed to be Level III which is ‘Tolerable Risk’


(Doc. #: D370-1459 Rev. 2.0)



Based on the outcomes of all of the above, the overall conclusion of the risk-benefit determination for the present device range is as follows:

ResMed has evaluated the medical benefits to the patient, overall residual risk associated with the use and materials analysis of the ResMed bilevel PAP units for OSA. The conclusion of this evaluation, based on review of published evidence currently available and taking into account the intended purpose and state of the art, is that the medical benefits of the bilevel PAP devices for OSA and associated accessories are Benefit Class I and outweigh the residual risk.

This clinical evaluation therefore concludes that the potential risks identified for an AirCurve 10 device are adequately addressed with the overall risk-benefit ratio for the AirCurve 10 range and accessories being shown to be favourable, in line with the state of the art, and compliant with MDR’s 2017/745 General Safety and Performance Requirements #2, #3, #4, #8 and #10. This is in keeping with the patient population and the underlying disease being treated being of relatively low risk.


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4.6.3 Requirement on performance

MDR’s 2017/745 General Safety and Performance Requirements #1 states that:

(1) Devices shall achieve the performance intended by their manufacturer and shall be designed and manufactured in such a way that, during normal conditions of use, they are suitable for their intended purpose […].

Specific claims made by ResMed on overall product performance of AirCurve 10 devices include (see 2.7 for full list):

A. AIRCURVE 10 DEVICES ENABLE RELIABLE DELIVERY OF THERAPY PRESSURE.

B. AIRCURVE DEVICES ARE IDEAL FOR OSA PATIENTS WHO FIND IT DIFFICULT TO ADJUST TO CPAP OR REQUIRE EXTRA SUPPORT.

C. AIRCURVE 10 DEVICES REDUCE THE WORK OF BREATHING SO PATIENTS REMAIN COMFORTABLE.

D. AIRCURVE 10 DEVICES HELP TREAT CHALLENGING OSA PATIENTS.

E. AIRCURVE’S BUILT-IN WIRELESS TECHNOLOGY (AIRVIEW AND MYAIR) AND COMPATIBILITY WITH SPECIALISED SOFTWARE (RESSCAN) OFFERS A WIDE RANGE OF INFORMATION THAT HELPS PATIENTS STAY ON TRACK WITH TREATMENT.

Type of evidence

Document reference

Devices Relevant elements

tested Outcome GSPRs

Related to specific

claim


ISO 80601-2-70:2015 Compliance report internal

ref. 1

AirCurve 10

Particular requirements for basic safety and essential performance of sleep apnoea breathing therapy equipment:

• Compliance with ISO 4871:1996 and ISO 3744:2010 on how to measure sound pressure levels

• Methods to test stable delivery of static and dynamic airway pressure accuracy for each therapy mode

• Methods to test maximum flowrate capabilities

• Not exceeding the maximum limited pressure

• Minimised rebreathing of CO2

Pass (1) A


TUV SUD test report on respiratory flow generator internal ref. 26

AirCurve 10 Pass (1) A


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Type of evidence

Document reference



Related to specific

claim

System verification


AirCurve 10

To address the verification and validation activities which apply to the proper functioning of the device and its accessories (4.3.3.2).

Pass (1) A

System verification

Preclinical bench test reports: Open loop Therapy Verification (4.3.3.4.2)

AirCurve 10

To test that individual aspects of therapy algorithms perform as intended and to predetermined performance standards.

Pass (1) A, B

Clinical investigation

Preclinical bench test reports: Closed loop Therapy Validation (4.3.3.4.3)

AirCurve 10

To test that all therapy functions provide adequate therapy under realistic conditions.

Pass (see internal ref. 46 for results)

(1) A, B, C


PMCF study (Malhotra et al. (17))

AirCurve 10

To analyse the effect of a patient engagement tool on PAP adherence (4.3.2.1).

Patient engagement tool (myAir) plus telemonitoring (AirView) was associated with sig. higher treatment adherence vs. telemonitoring alone. Normalised AHI (<5) in both groups of PAP-treated patients.

(1) A, D, E


PMCF study (Woehrle et al. (18))

AirCurve 10

To analyse the effect of a patient engagement tool on PAP adherence (4.3.2.1).

Patient engagement tool (myAir) plus telemonitoring (AirView) was associated with sig. higher treatment adherence vs. telemonitoring alone. Normalised AHI (<5) in both groups of PAP-treated patients.

(1) A, D, E


(Doc. #: D370-1459 Rev. 2.0)



Type of evidence

Document reference



Related to specific

claim


PMCF study (Pepin et al. (65))

AirCurve 10

To assess whether switching from PAP to ASV improves adherence rates (4.3.2.1).

Switch to ASV sig. improved adherence.

(1) -


PMCF study (Benjafield et al. (66))

AirCurve 10 S and AirCurve 10 VAuto

To compare PAP therapy usage data of non-compliant OSA patients on PAP/APAP who were switched to bilevel PAP.

Device usage sig. increased after switch to bilevel PAP. Residual AHI also improved sig. after the switch.

(1) B, C, D


PMCF study (Cistulli et al. (67))

AirCurve 10 To assess 90-day CPAP adherence rates (4.3.2.1)

High adherence rates (75%) were observed.

(1) D


Ball et al. (21)

S7 VPAP Malibu (applicable to AirCurve 10 VAuto)

To compare whether the VAuto therapy algorithm is as efficacious as the standard bilevel mode.

VAuto is non-inferior to standard bilevel mode.

(1) A, B, C, D


Trend report AirCurve 10

Analysis of Product Field Performance based on total number of complaints (4.3.2.2.1).

AirCurve 10 reached target Product Field Performance.

(1) A

PAP therapy for OSA has a long history and is based on well-established technology and consistent claims with no significant innovative aspects. All PAP devices work by simple physiological mechanisms that involve generating low pressures of air delivered through the nasal or oronasal passages that keep the airway open during sleep. Verification testing undertaken for each device under evaluation confirm that the AirCurve 10 range of flow generators achieve their intended performance as aligned to the specific requirements of risk analysis, harmonised standards and product specifications under all normal operating conditions internal ref. 1, 26-27.

Given that PAP therapy works by simple physiological mechanisms, they can be reliably simulated with patient model bench testing. The suite of testing undertaken for the devices under evaluation verify individual performance aspects of the therapy algorithms (open loop testing) and validate therapy efficacy in virtual patient models (closed loop testing). Together, these tests provide stable and repeatable results that the AirCurve 10 series achieve their intended clinical performance.

Analyses of Product Field Performance, which record the monthly complaint rate per device in the field, showed that after an expected spike in complaints immediately following product release, the number of complaints for AirCurve 10 devices settled below the acceptable market performance. This was under 0.1% (less than 1 in 1000 AirCurve 10 devices generated a complaint / month).

Clinical investigations undertaken by ResMed and from the literature confirm the effectiveness of devices in the AirCurve 10 series in treating OSA. Four separate studies provide objective device data demonstrated that AHI was normalised in large cohorts of OSA patients treated in a real-world setting (involving over 2 million OSA patients) (17, 18, 66, 67). Non-inferiority of the VAuto therapy algorithm versus


(Doc. #: D370-1459 Rev. 2.0)



standard bilevel was demonstrated in a prospective randomized trial involving a predicate device but identical therapy algorithm (21). There is some evidence to suggest that there may be a potential benefit in switching from CPAP/APAP to bilevel PAP for patients struggling with treatment adherence (66). However, patients likely to develop central sleep apnoea during treatment may benefit from a switch from PAP to ASV (65).

Taken together, there is sufficient evidence in amount and quality to validate the ongoing performance of all AirCurve 10 devices on the market (GSPR 1) and its associated claims on overall product performance (A, B, C). Based on the outcomes of the appraisal of the supporting clinical data, the strength of the conclusion that performance requirements are fulfilled for AirCurve 10 devices is as follows:

A clinical benefit that can be ascertained from the clinical data is related to AirCurve 10 telemonitoring and active patient engagement capabilities. Telemonitoring with the devices under evaluation is more beneficial in improving treatment compliance compared to usual follow-up care supporting associated claims on compliance (D, E) (17, 18). Based on the outcomes of the appraisal of the supporting clinical data, the strength of this conclusion is as follows:

4.6.4 Requirement on acceptability of side-effects

MDR’s 2017/745 General Safety and Performance Requirement #6 states that:

(6) The characteristics and performance of a device shall not be adversely affected to such a degree that the health or safety of the patient or the user and, where applicable, of other persons are compromised during the lifetime of the device, as indicated by the manufacturer, when the device is subjected to the stresses which can occur during normal conditions of use and has been properly maintained in accordance with the manufacturer's instructions.

ResMed makes no device-specific claims on the side effects of the devices of concern (see 2.7 for a full list of claims).

Type of

evidence Document reference


GSPRs



AirCurve 10

Analysis any device malfunctions, deterioration in device performance, inadequate instructions, inadequate labelling resulting in death, serious injury or

A total of 3 vigilance reports were submitted since the launch of the devices on the market. No

(6)

Quality: Strong Consistency: Strong Quantity: Strong Contribution: Strong

Quality: Strong Consistency: Strong Quantity: Fair Contribution: Fair


(Doc. #: D370-1459 Rev. 2.0)



Type of evidence

Document reference


GSPRs serious deterioration in state of health.

unexpected risks were identified.



AirCurve 10

Analysis of all reported complaints captured in ResMed’s complaints management system.

The investigation based on complaints data concluded that the devices under evaluation did not cause or contribute to any serious adverse events since product launch.

(6)


Bilevel Sleep device-specific literature review internal ref.

47

AirCurve 10

To plan, search, appraise and analyse published clinical data related to ResMed’s range of bilevel PAP devices for OSA.

No safety concerns emerged from the clinical data involving the devices of concern.

(6)

Common side effects reported with PAP therapy use include pressure on the face, mask discomfort, air leak, dry upper airways, skin breakdown, nasal congestion, aerophagia and pressure intolerance (35, 41). Most side effects associated with PAP therapy can be corrected by interventions such as proper pressure titration, efficient mask fitting and the use of humidification (34, 35). In paediatric patients, the use of PAP is generally associated with few side effects, which are similar to those observed in adult patients (25). While the side effects of PAP do not pose a direct risk to the user, it can adversely affect treatment adherence.

One of the articles identified in the systematic literature search on the state-of-the-art, a 2006 Cochrane review (14), carried out pooled analyses of side effects associated with CPAP versus control with the following results:

CPAP (n/N) Control (n/N) Results from one parallel study: Mask discomfort 2/13 0/20 Sleep disturbance 1/13 0/20 Dry throat % nose 2/13 0/20 Rhinorrhoea 7/13 0/20 Result from two crossover studies: Early awakening 1/31 0/34 Sleep disturbance 8/34 0/34 Problems with mask/headgear 8/34 0/34 Difficulty falling asleep 1/34 0/34 Residual sleepiness 0/34 3/34 Dry/open mouth 4/34 0/34

While none of the studies directly investigated safety-related outcomes, none of the studies involving human participants identified complications internal ref. 47.


(Doc. #: D370-1459 Rev. 2.0)



ResMed carries out investigations into side effects in the form of postmarket surveillance of devices. Since the launch of the devices under evaluation, 38 complaints were categorised as Category 1, consisting of death (2), injury (16), fire/flame (17), mislabel (3). Both death reports were deemed not related to the device and no fault was found in the returned devices. However, PAP devices do not have Essential Performance.

Analyses of all complaints data found desaturation and burn accounting to be the two most common types of injuries reported to ResMed, with three cases each, followed by respiratory infections (2), cardiovascular symptoms (2) and hospitalisation incidents (2). All were investigated and none of the reported injuries were caused or contributed to by the intended performance of the device for there are no known physiological links between these conditions and PAP therapy.

From the three vigilance reports since the launch of the devices, investigations did not find any device malfunction in two of the cases (hospitalisation due to desaturation and stroke) and in the third case (fire), the device was not returned and could not be tested.

The evaluation of postmarket data identified no unexpected side effects associated with the use of AirCurve 10 devices. It confirms low severity and frequency of potential undesirable side effects, which is in line with the published literature and general state-of-the-art for PAP therapy. Any side effects associated with the use of an AirCurve 10 model constitute an acceptable risk when weighed against the performances intended (GSPR 6).

Quality: Strong Consistency: Strong Quantity: Fair Contribution: Strong


(Doc. #: D370-1459 Rev. 2.0)



5. CONCLUSION

This clinical evaluation report served to assess whether the AirCurve 10 range of bilevel PAP devices for OSA manufactured by ResMed are in conformity with all applicable General Safety and Performance Requirements.

ResMed is able to demonstrate compliance with the General Safety and Performance Requirements by meeting the requirements of internationally recognised harmonised standards without the need for additional clinical data. However, the ongoing clinical performance and clinical safety of AirCurve 10 devices on the market has been verified by the additional clinical data identified in this report. These clinical data have included patient model bench tests, PMCF studies, clinical experience data and usability evaluations undertaken by ResMed, as well as clinical data from the literature involving the devices of concern.

The existing data have been determined to be sufficient in amount and quality to verify that the devices are in conformity with the applicable General Safety and Performance Requirements:

– Usability evaluations show that the product design adequately reduces the risk of use error as far as possible and that the design is adequate for the intended users.

– In addition to fundamental system verification testing, ResMed undertakes a suite of patient model bench tests that assess the performance of all aspects of therapy. Patient model bench tests are particularly suited for confirming simple physiological mechanisms like the pneumatic air splint achieved by PAP therapy in stable and repeatable settings.

– PMCF studies and clinical data from the literature further demonstrate adequate safety and performance of AirCurve 10 devices in large OSA patient cohorts in laboratory and real-world settings.

– Studies involving the same patient cohorts demonstrate positive effects of telemonitoring and patient engagement tools (as featured in AirCurve 10 devices) on treatment adherence, which is consistently cited as the single main issue with PAP therapy.

– A wealth of clinical experience data collected from users of AirCurve 10 devices (since the launch of the devices in 2014) has further confirmed their long-term safety and performance.

There is a high degree of consistency between the clinical data listed above. No discrepancies or unanswered question were identified that need to be addressed with PMS activities.

Clinical claims foreseen by ResMed are identified and any discrepancy and gaps are fully covered by clinical data.

The intended use and corresponding risk reduction measures are adequate and a clinical appraisal of product labelling has deemed it suitable for the intended users and all usability aspects. There is full consistency between the clinical data, the information materials supplied by the manufacturer and the risk management documentation for the devices under evaluation.

The benefit/risk profile according to current knowledge in the medical fields concerned and according to available medical alternatives is deemed acceptable. The potential risks identified for AirCurve 10 devices are adequately addressed and the overall risk-benefit ratio for AirCurve 10 devices and their accessories is favourable.

The evaluation and summation of the available clinical data provided demonstrates that the AirCurve 10 range of bilevel PAP devices for OSA including accessories is suitable for the stated intended use and there are no clinical objections to their ongoing marketing and supply. Conformity to the General Safety and Performance Requirements is reliably demonstrated.


(Doc. #: D370-1459 Rev. 2.0)



Clinical expert comment: The information contained in the state of the art section of this clinical evaluation report provides comprehensive information about the use of PAP devices for the treatment of OSA and identifies that the performance and safety of such PAP devices is well-established. Given that the performance and safety of PAP devices for the treatment of OSA is well-established, ResMed has determined that demonstration of conformity with General Safety and Performance Requirements based on clinical data is not deemed appropriate. The risk management documentation for the PAP devices is in line with this determination, as none of the identified hazards required clinical data in order to be mitigated. Demonstration of conformity with the General Safety and Performance Requirements has been adequately undertaken based on performance evaluation, bench testing, and pre-clinical evaluation, as well as the information supplied with the PAP devices. There are no clinical objections to the ongoing marketing and supply of these devices.


(Doc. #: D370-1459 Rev. 2.0)



6. IDENTIFICATION OF EVALUATORS

Sophia Karok, PhD

Role: Author and Medical Writer

Relevant background: PhD in Physiology and Neuroscience and 5 years medical writing experience.

Sophia-Karok_CV.docx

Martin Devitt, BMED, GAICD

Role: Consultant Medical Director (Clinical expert comment)

Relevant background: Practising emergency physician, former Head of the Medical Devices Clinical Section at the TGA, expert clinical and regulatory consultant in medical devices and IVDs.

Martin-Devitt_CV.pdf

Alison Hansford, BSc, MAppSc, MScMed, CRFS

Role: Medical Information Manager

Relevant background: Sleep and respiratory scientist with over 30 years’ clinical and research experience in the field of Thoracic and Sleep Medicine in the hospital and medical device environment. Experienced in medical information, education and writing, as well as clinical study management.

Alison-Hansford_CV.doc

Lily Lai, BAppSc, MHS

Role: Postmarket Data Specialist

Relevant background: Over 10 years’ experience as a Senior Physiotherapist and Clinical Specialist.

Lily-Lai-CV.pdf

Simon Lewi, BVSc

Role: Regulatory Expert


(Doc. #: D370-1459 Rev. 2.0)



Relevant background: Over 10 years’ experience in medical device Regulatory Affairs and Medical Affairs.

Simon-Lewi_CV.pdf

Carlos Nunez, MD

Role: Chief Medical Officer

Relevant background: Over 25 years’ experience in Clinical Practice including Anaesthesiology (Lifetime Diplomat, American Board of Anaesthesiology), Critical Care Medicine, Biomedical Informatics and Chief Medical Officer in medical device companies.

Carlos-Nunez_CV.pdf

6.1 Conflict of Interest Statement/s of the Author/s

All evaluators identified in section 6 are ResMed employees. There are no other conflicts of interest to declare.


(Doc. #: D370-1459 Rev. 2.0)



7. APPENDICES

7.1 Appendix 1: References

7.1.1 Internal References

1. eLB0989-804 Analysis of Newport Compliance to ISO 80601-2-70:2015 based on Witness Test Results

2. A3354890 AirCurve 10 ST User Guide (device with humidifier)

3. A4279048 AirCurve 10 S and AirCurve 10 VAuto User Guide (device with humidifier)

4. D370-1461 Bilevel Sleep CEP

5. 1018392r2 AirCurve 10 S FS EU ENG LOW (Obj C169399)

6. 1018393r2 AirCurve 10 ST FS EU ENG LOW (Obj C169402)

7. 1018394r3 AirCurve 10 VAutoFS EU ENG LOW (Obj C169406)

8. D370-009 Newport FG System Specification

9. D370-000 Newport MRD

10. D370-030 Newport Clinical Requirements Document (Bilevel)

11. D222-009 Manufacturing Requirements S8 Modules (includes AirView software spec)

12. A1436094 Heated Tubing User Clinical Trial Final Report

13. D360-067 Nexus Heated Tube and Humidifier Clinical Trial Report

14. D370-016 Newport Humidifier System Specification

15. D313-040 ResScan System Requirements Specification

16. D000-0167 Misc Algorithm Definitions Arising From Nexus and VPAP Clinical

17. A954392 Electret (Electrostatic Hypoallergenic Pollen Filters)100-550gm

18. D370-1471 Newport/Juno Material Substance Report

19. eLB0897-188 Particulates Test Details for Newport Flow Generator

20. eLB0897-189 Volatiles Test Details for Newport Flow Generator

21. C266015 Bilevel Sleep SoTA literature review

22. AF101-016-01 Literature Searching Plan, Report and Assessment

23. D370-062 Newport VPAP ST Risk Analysis Summary Report

24. GQT630-00-01 Risk Scales

25. D370-1463 Bilevel Sleep Risk-Benefit Analysis

26. A4058465 TUV SUD test report on respiratory flow generator (Newport)

27. D370-1291 System V&V Summary Report (Newport)

28. D370-1178 Verification Summary Report for FPL (Newport)

29. D370-1354 Newport Regression Analysis (Sx567-0304)

30. D370-3106 Newport Regression Analysis Test Plan Protocol and Report for Juno Compatible PCBA


(Doc. #: D370-1459 Rev. 2.0)



31. D370-1314 Newport System Regression Analysis (CPL to FPL1)

32. D370-103 Newport Usability Evaluation Report (1) - User Interface

33. D370-104 Newport Usability Evaluation Report (2) - Humidifier Tub

34. D370-109 Newport Usability Evaluation Report (3) - Humidifier tub v2/tubing

35. D370-151 Newport Usability Evaluation Report (4) - Clinician UI

36. D370-153 Newport Usability Evaluation Report (5) - Tubing Connection

37. D370-154 Newport Usability Evaluation Report (6) - Humidifier Tub V3

38. D370-1225 Newport Usability Evaluation 7 and Usability Evaluation 8 Report-Humidifier Tub Invesitgations

39. D370-1226 Newport Usability Evaluation 7 Report- PAP Device System Investigations

40. D370-1227 Newport Usability Evaluation 7 - Tubing Investigations

41. D370-1235 Newport Usability Evaluation (9) (System Usability- Patients) Report

42. D370-1236 Newport Usability Evaluation (10) (System Usability- Clinicians) Report

43. D370-1245 Newport Usability Evaluation 12 Report

44. D370-1279 Newport Usability Evaluation 14 Report

45. D370-019 Usability FMEA (Newport)

46. D370-1288 S9 Wanda Test Results Summary of Performance Testing

47. C266070 Bilevel Sleep device-specific literature review

48. AWI137-001 Clinical Trials and Usability Evaluations at ResMed

49. Evidence Analysis Library from the Academy of Nutrition and Dietetics. Retrieved 03/09/2018

https://www.andeal.org/vault/2440/web/files/EAL_Grading_Table.pdf#

50. D005-006 Position statement on Newport: Nanoparticles

51. D370-1471 Material Substances Assessment Report - Newport/Juno

52. D370-407 Newport materials: Suitability for use with respect to patient safety and risk of harm

53. eLB0320-958 Assessment of Diazene-1,2-dicarboxamide (ADCA) in: Meiban’s tubes, mask sub-assemblies and Air10 elbow

54. eLB0320-1071 Assessment of substance of very high concern (SVHC): In products including Newport products

55. eLB0320-1157 Assessment of Phenol, 2-(2H-benzotriazol-2-yl)-4,6-bis(1,1-dimethylpropyl):In Newport flow plate and H5i chassis

56. eLB1018-036 Clinical Appraisal of Labelling Mitigations - Newport (Bilevel)

57. D370-1469 Bilevel Sleep PMCF Report

58. D370-1468 Bilevel Sleep PMCF Plan

7.1.2 External References


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