ESTEEM TOTALLY IMPLANTABLE HEARING SYSTEM

P090018 · Envoy Medical Corporation · OAF · Mar 17, 2010 · Ear, Nose, Throat

Device Facts

Record IDP090018
Device NameESTEEM TOTALLY IMPLANTABLE HEARING SYSTEM
ApplicantEnvoy Medical Corporation
Product CodeOAF · Ear, Nose, Throat
Decision DateMar 17, 2010
DecisionAPPR
Device ClassClass 3
AttributesTherapeutic, Expedited Review

Indications for Use

The Esteem is intended to alleviate hearing loss in patients by replicating the ossicular chain and providing additional gain. The Esteem is indicated for patients with hearing loss that meet the following criteria: 18 years of age or older Stable bilateral sensorineural hearing loss Moderate to severe sensorineural hearing loss defined by Pure Tone Average (PTA) Unaided speech discrimination test score greater than or equal to 40% Normally functioning of Eustachian tube Normal middle ear anatomy Normal tympanic membrane Adequate space for Esteem implant determined via high resolution CT scan Minimum 30 days of experience with appropriately fit hearing aids.

Device Story

Esteem is a totally implantable middle ear hearing device. A piezoelectric sensor attached to the incus bone detects tympanic membrane/ossicular vibrations and converts them into electrical signals. A sound processor, implanted in the temporal bone, amplifies and filters these signals based on the patient's hearing loss profile. A piezoelectric driver, attached to the stapes/incus, converts the processed electrical signals back into mechanical vibrations, which are delivered to the cochlea. The system includes external instruments: an Esteem Programmer (portable computer with telemetry wand) for clinician programming, a Personal Programmer for patient volume/setting adjustments, and an Intraoperative System Analyzer for surgical verification. The device is used in a clinical/surgical setting by otolaryngologists. By bypassing the external ear canal and directly stimulating the ossicular chain, the device aims to provide improved sound clarity and speech understanding in background noise compared to traditional acoustic hearing aids, offering a discreet, invisible solution for patients with moderate-to-severe sensorineural hearing loss.

Clinical Evidence

Pivotal prospective, multi-center, one-arm, non-randomized trial (IDE G070162) of 57 implanted subjects. Primary endpoints: Serious Adverse Device Effects (SADE), cochlear stability (bone conduction thresholds), Speech Reception Threshold (SRT), and Word Recognition Scores (WRS). Results at 4 months: 10.5% SADE rate; 5.3% device failure rate. Mean SRT improvement of 10.6 dB (95% CI 7.1-14.2). 93% of subjects had WRS equal to or better than pre-implant aided condition. Bone conduction remained stable. Common adverse events included taste disturbance (42%), middle ear effusion (32%), and facial paresis/paralysis (7%).

Technological Characteristics

Totally implantable middle ear hearing device. Materials: silicone rubber, polyurethane, stainless steel, titanium, gold. Sensing/actuation: piezoelectric transducers. Energy source: implanted battery (5-year longevity). Connectivity: bi-directional telemetry for programming. Sterilization: EtO (components), Gamma (EnvoyCem). Software: embedded firmware for signal processing and external programmer software for configuration.

Indications for Use

Indicated for patients 18+ years old with stable bilateral moderate-to-severe sensorineural hearing loss, unaided speech discrimination score >=40%, normal Eustachian tube/middle ear anatomy/tympanic membrane, adequate implant space via CT, and 30+ days experience with hearing aids. Contraindicated for history of chronic middle ear infections, inner ear disorders, fluctuating hearing loss, otitis externa, cholesteatoma, retrocochlear disorders, disabling tinnitus, keloid formation, hypersensitivity to device materials, conditions affecting healing, or pregnancy.

Regulatory Classification

Identification

Intended to provide useful hearing to persons with sensorineural hearing loss. Indicated for adults with mild to severe sensorineural hearing loss who have a speech discrimination score greater than or equal to 60%.

Submission Summary (Full Text)

{0} SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) I. GENERAL INFORMATION Device Generic Name: Implantable Middle Ear Hearing Device Device Trade Name: Esteem®, consisting of: Sound Processor Model 2001 Sensor Model 7002 Driver Model 7502 Esteem Programmer Model 6001 Personal Programmer Model 8001 Intraoperative System Analyzer Model 3001 Accessories Applicant's Name and Address: Envoy Medical Corporation 5000 Township Parkway St. Paul, MN 55110 Date of Panel Recommendation: December 18, 2009 Premarket Application (PMA) Number: P090018 Date of FDA Notice of Approval: March 17, 2010 Expedited: Granted expedited review status on August 27, 2009 because the Esteem® represents a breakthrough technology which provides an alternative to non-implantable and partially implantable hearing aid technology. II. INDICATIONS FOR USE The Esteem is intended to alleviate hearing loss in patients by replicating the ossicular chain and providing additional gain. The Esteem is indicated for patients with hearing loss that meet the following criteria: - 18 years of age or older - Stable bilateral sensorineural hearing loss - Moderate to severe sensorineural hearing loss defined by Pure Tone Average (PTA) - Unaided speech discrimination test score greater than or equal to 40% - Normally functioning of Eustachian tube - Normal middle ear anatomy - Normal tympanic membrane - Adequate space for Esteem implant determined via high resolution CT scan - Minimum 30 days of experience with appropriately fit hearing aids. PMA P090018: FDA Summary of Safety and Effectiveness Data {1} # III. CONTRAINDICATIONS Esteem® is contraindicated under the following conditions: - History of post-adolescent chronic middle ear infections, inner ear disorders or recurring vertigo requiring treatment, disorders such as mastoiditis, Hydrops or Meniere’s syndrome or disease - Known history of fluctuating air conduction and/or bone conduction hearing loss over the past one year period of 15 dB in either direction at 2 or more frequencies (from 500 to 4000 Hz) - History of otitis externa or eczema for the outer ear canal - Cholesteatoma or destructive middle ear disease - Retrocochlear or central auditory disorders - Disabling tinnitus, defined as tinnitus which requires treatment - History of keloid formation - Hypersensitivity to silicone rubber, polyurethane, stainless steel, titanium and/or gold - A pre-existing medical condition or undergoing a treatment that may affect healing process - During pregnancy # IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the Esteem® labeling. # V. DEVICE DESCRIPTION The Esteem is a totally implantable middle ear hearing device. The Esteem consists of three implantable components, the Sound Processor, the Sensor and the Driver, and external instruments for interrogating, testing and programming the Esteem. Specifically, the Esteem includes the Model 2001 Sound Processor, Sensor Model 7002, Driver Model 7502, Esteem Programmer Model 6001 with Esteem Programmer Software and Wand, Personal Programmer Model 8001, Intraoperative System Analyzer Model 3001, and accessories. Implantable Components: 1. Sensor: The piezoelectric Sensor tip is attached to the incus bone. The Sensor senses vibrations from the tympanic membrane and malleus/incus and converts these mechanical vibrations into electrical signals that are sent to the Sound Processor (Fig. 1). 2. Sound Processor: The Sound Processor, which is implanted in the temporal bone and connected to the Sensor and Driver via leads, receives the electrical signal from the Sensor, amplifies and filters the signal to compensate for the patient’s hearing loss profile. The enhanced signal is then sent to the Driver (Fig. 1). 3. Driver: The piezoelectric Driver tip is attached to the stapes/incus bone. The Driver converts the enhanced electrical signal received from the Sound Processor back to PMA P090018: FDA Summary of Safety and Effectiveness Data {2} mechanical energy, i. e. vibrations. The vibrations are transferred to the stapes and delivered as sound waves in the cochlea (Fig.1). ![img-0.jpeg](img-0.jpeg) Figure 1. Implantable Esteem components. ## External Instruments: 1. Esteem Programmer: This portable computer with the Esteem Programmer Software and a bi-directional telemetry wand is used to interrogate the implanted Sound Processor and to program it to a custom prescription for each patient. 2. Personal Programmer: This remote control device is used by the patient to adjust the volume and select pre-programmed settings in the Sound Processor. 3. Intraoperative System Analyzer: The ISA is a test system, consisting of a computer, software, Patient Interface Device and cables, used to verify the function of the implantable components during the implant procedure. ## Accessories: 1. Unique Accessories: Several unique accessories are used during the implantation of the Esteem. The Glasscock Stabilizer is a sterile temporary retainer used to position and stabilize the Sensor and Driver during implant. The Replica Sound Processor is a tool used by the implanting physician to assess the space and placement requirements for the implantable Sound Processor. EnvoyCem is cement used to bond the Sensor and Driver PMA P090018: FDA Summary of Safety and Effectiveness Data {3} tips to the ossicular chain. MedCem is bone cement used to anchor the Sensor and Driver to the mastoid floor during implant. 2. Standard Surgical Accessories: The surgical team may use several commercially available accessories that are either FDA cleared or exempt during the implant of the Esteem. These include bone screws, screwdriver, pliers, pick, syringes and sterilization tray. Please refer to the Operator’s Manual for additional details. ## VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for the correction of hearing loss. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle. Alternate practices and procedures include acoustic hearing aids and semi-implantable middle ear hearing devices. Hearing aids can be worn in a variety of configurations, including behind the ear, in the ear, in the canal or completely in the ear canal. Semi-implantable middle ear hearing devices typically consist of a middle ear implant and an external sound processing unit worn in and/or behind the ear. ## VII. MARKETING HISTORY The Esteem received CE Mark certification approval May 3, 2006. Since market introduction, Envoy Medical has distributed approximately 85-100 Esteem devices throughout the European Union and Switzerland. In addition, approximately 20 Esteem devices have been distributed in India, Iran and Brazil since introduction in early 2008. The Esteem was also granted a Canadian License in March 2008 but no Esteem devices have been distributed to date. The Esteem has not been withdrawn from any market for any reason related to safety or effectiveness. ## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device. Surgery of the middle ear to implant the Esteem involves manipulation and dissection of the ossicular chain (incus, malleus, and stapes) and exposes the inner ear to the risk of surgical trauma. Serious complications may occur during or after the surgery that may include, but are not limited to: - loss in residual hearing due to surgical trauma - device displacement after surgery, - tissue buildup causing feedback or limited benefit - device failure PMA P090018: FDA Summary of Safety and Effectiveness Data page 4 9 {4} - infection after surgery. Additional complications include: - swelling - numbness and discomfort around the ear after surgery - facial paralysis/paresis - taste disturbance - numbness of the tongue and face For the specific adverse events that occurred in the clinical studies, please see Section X. ## IX. SUMMARY OF PRECLINICAL STUDIES ### A. Laboratory Studies #### Biocompatibility Biocompatibility testing was conducted on all body contacting materials prepared to represent the finished device, as it would be implanted in the patient. All toxicity endpoints recommended for evaluation by ISO 10993-1: 2003 Biological Evaluation of Medical and Dental Materials and Devices, Part 1: Guidance on Selection of Tests and FDA Blue Book memorandum G95-1 were addressed. Tests conducted fall into the ISO guidance category for permanent (&gt;30 days) implantable, bone and tissue contacting devices. In addition, all materials used in the implant accessory devices were subjected to tests in accordance to the ISO Guidance category for implant devices contacting tissue/bone for a limited (&lt;24 hours) duration. All results for cytotoxicity, sensitization, implantation, chronic/acute toxicity and carcinogenicity were acceptable. Implanted System Assemblies/Materials - Permanent Exposure (&gt;30 Days) | Test | Test Method | Results | | --- | --- | --- | | Cytotoxicity – L929 MEM Elution | According to ISO 10993-5; The “in-vitro” biological reactivity of the L929 mouse fibroblast cell culture is determined in response to an extract of the test material. The cells are allowed to grow to sub-confluency in tissue culture plates. An extract of the test material is prepared in Minimum Essential Media (MEM), which is transferred onto the cell layer. The plates are incubated for forty-eight hours at 37°C in a 5% Co_{2} incubator, and scored for reactivity at twenty-four and forty-eight hours. | The test article is considered non-cytotoxic and meets the requirements of ISO 10993-5 guidelines. | PMA P090018: FDA Summary of Safety and Effectiveness Data {5} PMA P090018: FDA Summary of Safety and Effectiveness Data page 6 | Test | Test Method | Results | | --- | --- | --- | | Sensitization - Klingman Maximization | According to ISO 10993-10; The test article will be exposed through test article extracts. Extracts of the test material are prepared in a (cotton seed oil) solution. The test begins with intradermal injections of Freund's Complete Adjuvant (FCA) and the test article. Seven days later the injection sites are covered with the test article or extract for a period of forty-eight hours. Fourteen days later a virgin site is challenged with a topical application of the test article or extract and scored at forty-eight hours. | Grade 1 reaction. A Grade 1 sensitization rate is not considered significant and the test article meets the requirements of the ISO 10993-10 guidelines. | | Irritation - Intracutaneous Injection | According to ISO 10993-10; The test article will be exposed through test article extracts. Extracts of the test material are prepared in a (cotton seed oil) solution. A minimum of two rabbits are injected intracutaneously with the test article and control materials. The injected sites are examined over a seventy-two hour period for evidence of tissue reaction such as erythema, edema, and necrosis. Observations are scored according to the Classification System for Scoring Skin Reactions (Draize scale). | The test article is considered a negligible irritant and meets the requirements of ISO 10993-10 guidelines. | | Acute Systemic Toxicity-Systemic Injection Test | According to ISO 10993-10; Mice are injected systemically with extracts of the test article in standard solutions (normal saline and cottonseed oil). The animals are observed for signs of toxicity immediately after injection and at 4, 24, 48 and 72 hours post injection. The requirements of the test are met if none of the animals treated with the test article extract have a significantly greater adverse reaction the animals treated with the vehicle control. | This test found no systemic toxicity and meets the requirements of ISO 10993-11 guidelines. | | Genotoxicity - Bacterial Reverse Mutation Assay | According to ISO 10993-3; The in-vitro assay is performed using Salmonella typhimurium to detect reverse mutations in histidine gene in a histidine-requiring strain to produce histidine-independence. Bacteria are plated onto histidine free medium and the plate is exposed to the test article extract. The plate is incubated and observed for growth after exposure. If the extract is showing mutagenic properties, reverse-mutated bacteria will now be able to grow on histidine free medium. The number of colonies is directly proportional to the mutagen potency. | The test article is considered non-mutagenic and meets the requirements of ISO 10993-3 guidelines. | {6} | Test | Test Method | Results | | --- | --- | --- | | Genotoxicity - Mouse Lymphoma Assay | According to ISO 10993-3; The test article is administered in vitro, through a solvent compatible with the test system. At least 200 metaphase cells will be analyzed for each test article extract and negative control. | The test article is considered non-mutagenic and meets the requirements of ISO 10993-3 guidelines. | | Genotoxicity - DNA-Effects-Rodent Micronucleus Assay | According to ISO 10993-3; The in-vivo assay is performed by exposing the bone marrow of mice to the test article extract. The bone marrow is collected at predetermined harvest times (24 and 48 hours after treatment). Bone marrow smears are prepared and analyzed for the presence of micronuclei. | The test article is considered non-mutagenic and meets the requirements of ISO 10993-3 guidelines. | | Implantation - Short and Long Term | According to ISO 10993-6; Test and control material is implanted into the paravertebral muscle (for Intramuscular implants) of each of three rabbits. At the end of the observation period, the area of the tissue surrounding the center position of each implant strip will be examined macroscopically. Following gross observations, a veterinary pathologist will process the implanted sites for histopathologic evaluation. Inflammation, fibrosis, hemorrhagic and necrosis are evaluated on a scale and compared to the control article sites. Short Term = 2 weeks Long Term = 12 weeks | The test article is considered a non-irritant and meets the requirements of ISO 10993-6 guidelines. | Tissue/Bone Contacting Accessories/Materials - Limited Exposure (&lt;24 hours) | Test | Test Method | Results | | --- | --- | --- | | Cytotoxicity - L929 MEM Elution | According to ISO 10993-5; The "in-vitro" biological reactivity of the L929 mouse fibroblast cell culture is determined in response to an extract of the test material. The cells are allowed to grow to sub-confluency in tissue culture plates. An extract of the test material is prepared in Minimum Essential Media (MEM), which is transferred onto the cell layer. The plates are incubated for forty-eight hours at 37°C in a 5% Co2 incubator, and scored for reactivity at twenty-four and forty-eight hours. | The test article is considered non-cytotoxic and meets the requirements of ISO 10993-5 guidelines. | PMA P090018: FDA Summary of Safety and Effectiveness Data {7} PMA P090018: FDA Summary of Safety and Effectiveness Data page 8 | Test | Test Method | Results | | --- | --- | --- | | Sensitization - Klingman Maximization | According to ISO 10993-10; The test article will be exposed through test article extracts. Extracts of the test material are prepared in a (cotton seed oil) solution. The test begins with intradermal injections of Freund's Complete Adjuvant (FCA) and the test article. Seven days later the injection sites are covered with the test article or extract for a period of forty-eight hours. Fourteen days later a virgin site is challenged with a topical application of the test article or extract and scored at forty-eight hours. | Grade 1 reaction. A Grade 1 sensitization rate is not considered significant and the test article meets the requirements of the ISO 10993-10 guidelines. | | Irritation - Intracutaneous Reactivity | According to ISO 10993-10; The test article will be exposed through test article extracts. Extracts of the test material are prepared in a (cotton seed oil) solution. A minimum of two rabbits are injected intracutaneously with the test article and control materials. The injected sites are examined over a seventy-two hour period for evidence of tissue reaction such as erythema, edema, and necrosis. Observations are scored according to the Classification System for Scoring Skin Reactions (Draize scale). | The test article is considered a negligible irritant and meets the requirements of ISO 10993-10 guidelines | | Acute Systemic Toxicity-Systemic Injection Test | According to ISO 10993-10; Mice are injected systemically with extracts of the test article in standard solutions (normal saline and cottonseed oil). The animals are observed for signs of toxicity immediately after injection and at 4, 24, 48 and 72 hours post injection. The requirements of the test are met if none of the animals treated with the test article extract have a significantly greater adverse reaction the animals treated with the vehicle control. | This test found no systemic toxicity and meets the requirements of ISO 10993-11 guidelines. | {8} # Electrical Testing Extensive testing was conducted on the Esteem to verify the design criteria and device performance with respect to the electrical properties and specifications in support of its safety and effectiveness. 1. Implantable Components: | Test | Requirement | Results | | --- | --- | --- | | Lead Continuity Resistance | Non-hermetic electrical connections between implanted system components shall have a combined series resistance of less than 50 ohms. | Passed | | Lead Isolation Resistance | Non-hermetic electrical connections between implanted system components shall maintain a minimum isolation resistance of at least 5 mega-ohms. | Passed | | Harmonic Distortion | The device shall exhibit less than 10% harmonic distortion for nominal signals as tested per ANSI S3.22 1996 | Passed | | Input Noise | Total input-referred rms noise shall be less than 25 dB SPL over the range 200 Hz to 8000 Hz | Passed | | Volume Control | Volume shall be programmable over at least a 21 dB range. | Passed | | Programmable Output Limiting | Maximum output level shall be programmable over at least a 12 dB range. | Passed | | Confirmation Tone | The implanted system shall output a confirmation tone after a valid communication from the external programmer. | Passed | | Implanted Battery Longevity | The implanted battery life shall be at least 5.0 years of typical operation, including a 1.0 year shelf life. | Passed | | BERI to EOL Operation | The device shall continue to function for 14 days of typical operation after initial Battery Elective Replacement Indicator (BERI) | Passed | | Heat Generation | In normal operation or any single fault condition, no outer surface of the device shall be more than 2°C above surrounding tissue temperature at 37°C. | Passed | | Implant Electromagnetic Sensitivity | In electromagnetic environments (EN 60601-1-2 or ANSI/AAMI PC69) the implanted components of the system shall not generate an output exceeding an equivalent input audio level of 85 dB SPL at 1kHz. | Passed | | Implant Electromagnetic Data Integrity | In electromagnetic environments (EN 60601-1-2 or ANSI/AAMI PC69) the implanted components of the system shall maintain internally stored data. | Passed | | Electrostatic Discharge | When subject to ESD exposure according to IEC 60601-1-2 Section 36.202.2, the implanted device shall exhibit no loss of internally stored data and no operational change. | Passed | | Identification | The implanted device shall store a unique serial number that can be interrogated by telemetry. | Passed | PMA P090018: FDA Summary of Safety and Effectiveness Data {9} PMA P090018: FDA Summary of Safety and Effectiveness Data page 10 # 2. External Components: | Test | Requirement | Results | | --- | --- | --- | | Electrostatic Discharge | After ESD exposure according to IEC 60601-1-2 and EN 45502-1, external components of the system will operate within normal limits. | Passed | | Radiated Emissions | External components of the system shall not transmit electromagnetic fields at levels above 30.0 dBuV/m in the range 30 – 230 MHz or above 37.0 dBuV/m in the range 230 – 1000 MHz. | Passed | | Radiated Immunity | The system shall provide means for ensuring integrity of transmissions between implant and external components in a 3 V/m electromagnetic environment over the range 80 MHz to 2.7 GHz. | Passed | # Mechanical Testing Extensive testing was conducted on the Esteem to verify the design criteria and device performance with respect to the mechanical properties and specifications in support of its safety and effectiveness. # 1. Implantable Components: | Test | Requirement | Results | | --- | --- | --- | | Lead Flex | Transducer leads to maintain continuity of 10 Ω or less following 82,000 flexural cycles at ±45° deflection. | Passed | | Hermeticity validation | Transducer & Sound Processors to be Hermetic to 1x10-8 atm cm3/s when tested per MIL-STD-883 and Validated Internal Test Methods | Passed | | Implantable components Shock and vibration | Implantable components in final packaging of to endure multiple drop sequences, implanted devices without packaging to endure vibration regimens per: EN 45502-1; 23.2. | Passed | | Packaging testing | Final Packaging to Endure simulated distribution-shipping conditions per ASTM D4169. | Passed | | Implantable components Operating and Storage Temperature | Implantable components to endure Storage Conditions of 0°C to 50°C and absolute humidity < 20 g/m3, and demonstrate operation in 35°C to 40°C with 30% to 100% Relative Humidity per EN 45502-1. | Passed | # 2. External Components: | Test | Requirement | Results | | --- | --- | --- | | Personal Programmer Shock & Vibration Testing | Personal Programmer to endure multiple drop sequences and vibration regimens 5-150 Hz 0.1 g2/Hz EN 45502-1; 23.1. | Passed | {10} | Test | Requirement | Results | | --- | --- | --- | | Personal Programmer Operating and Storage Conditions | Personal Programmer to endure Storage Conditions of -20°C to 60°C with and Relative Humidity from 15% to 95%, and demonstrate operation in 10°C to 30°C and Relative Humidity from 15% to 95%, as well as Absolute pressures spanning 700 hPa and 1060 hPa. per EN 45502-1. | Passed | | Esteem Programmer Operating Conditions | Esteem Programmer to demonstrate operation in 10°C to 30°C with Relative Humidity of 20% to 80%, non-condensing. | Passed | | Personal Programmer Spill-proof | Personal Programmer to demonstrate ability to endure a liquid spill, a drying sequence, and a 1 minute 2500 VDC over-voltage exposure, and remain functional. | Passed | ## Life Testing A series of *in vitro* life test studies were conducted on the Sensor and the Driver transducers, the Sound Processor, and the System as a whole under accelerated conditions to evaluate potential failure mechanisms. In addition, shelf life testing under accelerated and real-time conditions was conducted on sterile product in the final packaging configuration. | Test | Requirement | Results | | --- | --- | --- | | Transducer Mechanical Reliability | Transducers subjected to 37°C environment with accelerated actuation signal for failures associated with mechanical fatigue. Test must demonstrate 8-year reliable life with 90% reliability and 90% confidence. | Passed | | Transducer Environmental Reliability | Transducers subjected to elevated temperature/humidity/salinity environment with a typical drive signal providing a 16x Acceleration Factor for failures associated with exposure to the implanted environment. Test must demonstrate 8-year reliable life with 90% reliability and 90% confidence. | Passed | | Sound Processor Battery Life | Sound Processors must demonstrate that following Shelf-life, the longevity must be at least 4.0 years, 5.5 years, and 2.0 year of operation before reaching BERI for continuous use, typical use, and worst-case use conditions, respectively. | Passed & Exceeded | PMA P090018: FDA Summary of Safety and Effectiveness Data {11} # Shelf Life Testing: Accelerated and real time shelf life testing was conducted to validate a 2-year shelf life for all EtO sterilized components. For the Gamma sterilized EnvoyCem, accelerated shelf life testing was conducted to validate a 3-year shelf life. | Test | Requirement | Results | | --- | --- | --- | | Accelerated shelf life – Packaging & Devices | Packaging to demonstrate barrier integrity following Maximum EtO Sterilization, Expanded Range Temperature Storage Conditions (the Age Accelerating Factor), and ASTM D4169 – Distribution Cycle 13. Barrier Integrity verified with Visual Inspection, Dye Penetration, & Seal Strength Devices to remain functional. | Passed | | Real time shelf life – Packaging & Devices | Packaging to demonstrate barrier integrity following 2-year Real Time Testing in compliance with ISO 11607. Requiring packaging to satisfy requirements for: Visual Inspection, Dye Penetration, Seal Strength. | Passed | # Temporal Bone Testing: Temporal bone model was used to validate system performance. | Test | Requirement | Results | | --- | --- | --- | | Implanted System Output Capability | The implanted system shall be capable of generating stapes displacement of at least 100 nm p-p over the range 500 Hz to 2000 Hz in a typical temporal bone model. | Passed | | Output Limiting | The system shall be capable of limiting the maximum output displacement over at least a 20 dB range to accommodate patient physiology differences of efficacy and safety. | Passed | | Programmable System Gain Range | The system shall have a typical unaided vs. aided stapes displacement gain programmable over at least the range 0 dB to 40 dB for frequencies between 500 Hz and 2000 Hz in a typical temporal bone model. | Passed | PMA P090018: FDA Summary of Safety and Effectiveness Data {12} # Software Verification/Validation The Esteem Programmer, the Personal Programmer and the Intraoperative System Analyzer (ISA) contain software. Off-the-shelf software is used for the operating system for the Esteem Programmer and ISA. Software development was conducted in conformance to FDA Guidance for Industry on Off-The-Shelf Software Use in Medical Devices (1999). Level of concern for the software used in the Esteem instrument components is minor, based upon the FDA Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices (2005). | Test | Requirement | Results | | --- | --- | --- | | ISA Software | When used according to the labeling, the ISA software shall properly execute intraoperative measurements and display results. | Passed | | Personal Programmer Firmware | When used according to the labeling, the Personal Programmer software shall properly communicate with the implanted device and provide visual indicators for the patient. | Passed | | Esteem Programmer Software | When used according to the labeling, the Esteem Programmer software shall properly communicate with the implanted device, provide visual indicators for the clinician, and store programming information. | Passed | # Conclusions of Preclinical Studies The results of the Preclinical studies provided reasonable assurance that the Esteem system was safe for clinical studies and implantation in humans for its intended use. ## B. Animal Studies Early in the development of the Esteem, animal studies were conducted to research and evaluate the performance of the system. Prototype sensors were mounted in the middle ear of three chinchillas and followed for up to 98 days. Serial tympanometry and sensor voltage measurements were performed at three-week intervals. Results indicated that the chinchilla is a suitable model for long-term sensor implantation. The sensors appeared stable over time and frequency bandwidth. Histopathology showed no difference between the implanted ears and the controls. In order to verify the hermeticity and functionality of the Esteem under in vivo conditions, an animal implant study using a sheep was conducted. Four (4) Esteem devices, including Sound Processor, Sensor and Driver, were implanted in the back area of a sheep. Two (2) systems were explanted after 12 weeks and two (2) systems were explanted after 1 year. All systems were visually inspected and functionally tested after cleaning. There were no signs of corrosion or leakage noted; all functional testing indicated that the product performance was not affected by the in vivo implant conditions. PMA P090018: FDA Summary of Safety and Effectiveness Data {13} # X. SUMMARY OF PRIMARY CLINICAL STUDIES The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of the Esteem® device for alleviating hearing loss in subjects 18 years and older in the US under IDE # G070162. Data from this clinical study were the basis for the PMA approval decision. Additionally, the applicant performed an earlier clinical study (G000321) with the Esteem®. Although the PMA approval decision is based on G070162 alone, a description of both studies is given below. ## Study Description (G070162) In PMA submission P090018, the applicant presents data from a pivotal trial (IDE G070162) aimed at demonstrating the safety and effectiveness of the Esteem® system in subjects who have mild to severe hearing loss. This pivotal trial was designed as a prospective, multi-center, nonrandomized, clinical trial. Each of the 57 subjects implanted acted as both the test subject and the control by comparing his/her audiological test results and other measures prior to implant (under both unaided and aided conditions) to results at various time points after implantation. ## Regulatory History An earlier version of the Esteem® system was studied under a separate IDE (G000321). In the G000321 study, 72 total subjects were implanted at 6 investigational sites. Enrollment in this IDE has concluded. A number of G000321 subjects are now past their 3 and 4 year follow-ups. A high rate of failures (requiring 25 revision surgeries) was observed in this study, mainly due to inadequate bonding at the driver-stapes interface (17 events). The current Esteem® system was studied under the IDE G070162. In order to address the high rate of failures observed in G000321, “Best Practices” (BP) for cleaning and drying was developed and used in the G000321 clinical post-BP subjects. In addition to the BP steps, a new 2-step EnvoyCem attachment procedure for the Driver and improved ISA testing are unique improvements to device implantation in the G070162 study. In this study, 57 subjects were implanted at 3 investigational sites. Of the 57 implanted subjects, 52 are past the 10 month follow up. For a summary of key points of comparison between the G000321 study and the G070162 study, please refer to Table I below. PMA P090018: FDA Summary of Safety and Effectiveness Data page 14 19 {14} Table I. Key Points of Comparison between G070162 and G000321. | | G070162 | G000321 | | --- | --- | --- | | Principle of Operation | No change | - | | Device Design | Minor refinements of G000321 device, for example: • Single and dual channel frequency bands • Max gain 55 dB • Longevity 6 yrs nominal • Noise floor 23-28 dB SPL • Smaller personal programmer | • Single channel frequency band • Max gain 40 dB • Longevity 3.7 yrs nominal • Noise floor 30-35 dB SPL | | Surgical Technique | Enhanced intraoperative techniques • 2 step cementing • Improved ISA testing | • Single step cementing • Original ISA procedure | | Inclusion Criterion • Range of air conduction (AC) pure tone thresholds in the implanted ear • Speech discrimination test score | • Relatively wider (with respect to G000321) • > 40% | • Relatively more narrow (with respect to G070162) • > 60% | | Implanted Subjects | 57 | 72 | | 1^{st} Analysis of Endpoints | 4 month post-activation | 2 month post-activation | | Primary Effectiveness Endpoints | SRT and WRS are the co-primary effectiveness endpoints. | SRT is the only primary effectiveness endpoint. | | SRT Comparison (4 month post-activation) | Avg. 10.6 dB improvement (non-adjusted) | Avg. 3 dB improvement | | Primary Safety Endpoints • Failures • Bone Conduction Analysis | • 3 failures in 3 unique subjects • Forehead placement | • 25 failures in 20 unique subjects • Mastoid placement | The applicant sought approval for this PMA based on the clinical data obtained under the G070162 study. As discussed above, differences in the surgical procedures precluded pooling of safety and effectiveness data from the two studies. PMA P090018: FDA Summary of Safety and Effectiveness Data {15} PMA P090018: FDA Summary of Safety and Effectiveness Data page 16 21 # A. Study Design Patient treatments were begun on January 22, 2008 and the patients continue to be followed. The database for this PMA reflected data collected through July 31, 2009 and included 60 patients. There were three investigational sites. The study was a prospective, multi-center, one-arm, non-randomized, nonblinded study. The outcomes were compared to each subject’s baseline pre-implanted hearing aided condition. ## 1. Clinical Inclusion and Exclusion Criteria Enrollment in the G070162 study was limited to patients who met the following inclusion criteria: a) Subject is ≥ 18 years old. b) Subject understands the nature of the procedure and has signed the Subject Informed Consent Form prior to the procedure. c) Subject is willing and able to comply with specified follow-up evaluations and understands the audiological test procedures and use of the Esteem® System. d) Subject has mild to severe sensorineural hearing loss between 500 and 4000 Hz in the ear to be implanted with pure tone air conduction threshold levels within the limits of a Hearing Aid (HA) as follows: | Freq (Hz) | 500 | 1000 | 2000 | 3000 | 4000 | | --- | --- | --- | --- | --- | --- | | LL* (dB HL) | 30 | 35 | 35 | 35 | 35 | | UL* (dB HL) | 100 | 100 | 100 | 100 | 100 | *LL = Lower Level; UL = Upper Level e) Subject’s air-bone gap is no greater than 10 dB at 4 of the 5 following frequencies: 500, 1000, 2000, 3000 and 4000 Hz. f) Subject has an unaided maximum word recognition score of greater than or equal to 40% with recorded delivery using a phonetically balanced word list at SRT + 40 dB or at maximum tolerable presentation level. g) Subject is a current user of a properly functioning and appropriately fit hearing aid. This is defined as the subject has used this aid for at least four (4) hours (average) per day (in the ear to be implanted) for at least three (3) months for a new aid or one (1) month for an adjusted aid. h) Subject’s hearing aid, in the ear to be implanted, shall appropriately fit optimally. {16} i) Subject has normally functioning Eustachian tube. j) Subject has normal tympanic membrane. k) Subject has a normal middle ear anatomy. l) Subject has adequate space for Esteem® System implant determined via fine cut temporal bone CT scan. m) Subject is a native speaker of the English language. n) Subject is a hearing aid user in the ear to be implanted. Patients were not permitted to enroll in the G070162 study if they met any of the following exclusion criteria: a. Subject has a history of post-adolescent chronic middle ear infections, inner ear disorders or recurring vertigo requiring treatment, disorders such as mastoiditis, Hydrops or Meniere’s syndrome or disease. b. Subject has a history of otitis externa or eczema for the outer ear canal and the investigator believes this will affect the Esteem® System implantation. c. Subject has cholesteatoma or destructive middle ear disease. d. Subject has life expectancy of &lt; two (2) years due to other medical conditions. e. Subject has retrocochlear or central auditory disorders. f. Subject is known to be suffering from any psychological, developmental, physical, or emotional disorder that the investigator feels would interfere with the surgery or follow-up testing. g. Subject has a known history of fluctuating air conduction and/or bone conduction hearing loss over a one-year period of 15 dB in either direction at 2 or more frequencies (from 500 – 4000 Hz). h. Subject has sudden hearing loss due to unknown cause. i. Subject has a history of disabling tinnitus, defined as tinnitus which required treatment. j. Subject is unable to adequately perform audiological testing. PMA P090018: FDA Summary of Safety and Effectiveness Data page 17 {17} k. Subject has a medical condition or is undergoing a treatment that may affect healing and the investigator does not believe the subject is a good candidate for the trial. l. Subject has diabetes that is not well controlled with medication or diet and the investigator does not believe in his best medical judgment that the subject would be a good candidate for the trial. m. Subject is pregnant at the time of device implant. n. Subject has a history of keloid formation. o. Subject has known hypersensitivity to silicone. ## 2. Follow-up Schedule All patients were scheduled to return for follow-up examinations at 4 and 10 months postoperatively. Preoperative evaluations are listed in Table II. In this table, “Scr/BL” refers to the initial screening evaluation and baseline measurements. “Proc/Disc” refers to the surgical procedure. “On” and “Act” refer to turning on the device and activating (programming) the device, respectively. “I” refers to the implant side, whereas “N” refers to the non-implant side. The objective parameters measured postoperatively during the study are included in Table II. Clinical assessment occurred at 2 months, 4 months and 10 months post-operatively. In addition, clinical assessment occurred yearly. Adverse events and complications were recorded at all visits. Table II. Screening and Follow-Up Requirements. | | Scr/BL | Proc/Disc | On | Act | 2Mo | 4Mo Endpl | 10 Mo | Yearly | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Informed Consent | X | | | | | | | | | Medical History | X | | | | | | | | | Audiological and Hearing Aid History | X | | | | | | | | | Current Medications | X | X | X | X | X | X | X | X | | Adverse Events | | X | X | X | X | X | X | X | | Device Settings | | | X | X | X | X | X | X | PMA P090018: FDA Summary of Safety and Effectiveness Data {18} | Testing Requirements | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | | Otogram Pre-screen Audiogical Test | X | | | | | | | | APHAB Questionnaire | X | | | X | X | X | X | | Esteem Questionnaire | | | | X | X | X | X | | Otoscope Exam (perform prior to testing) | I | | I | I | I | I | I | | Tympanogram | I | | I | I | I | I | I | | Air Conduction Thresholds | I/N | | I | I | I/N | I/N | I | | Air Conduction - Aided (Implant) Ear Warble Tone | I | | | | | | | | Bone Conduction Thresholds | I/N | | I | I | I/N | I/N | I | | Most Comfortable Listening Level (MCL) | I/N | | | I | I | I | I | | Uncomfortable Listening Level (UCL) | I/N | | | I | I | I | I | | Speech Reception Threshold (SRT)- unaided | I/N | | | | | | | | Speech Reception Threshold (SRT)- aided | I/N | | | I | I | I | I | | | Scr / BL | Proc/ Disc | On | Act | 2Mo | 4Mo Endpt | 10 Mo | Yearly | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Word Recognition - unaided | I/N | | | | | | | | | Word Recognition - aided | I/N | | | I | I | I | I | I | | Quick SIN - Aided | I/N | | | I | I | I | I | I | | Quick SIN - Unaided | I/N | | | | | | | | | Envoygram IT | | | X | X | X | X | X | X | | CT Scan | X | | | | | | | | | X-ray of implanted device | | X | | | | | | | | | | | | | | | | | I=Implanted Ear N=Non-Implant Ear ## 3. Clinical Endpoints ### Co-Primary Safety Objective – Serious Adverse Device Effects To determine the incidence of Serious Adverse Device Effects (SADE) and the incidence rate of device failures and replacements. **Endpoints:** The analysis of the incidence of SADEs and device failures and replacements through the 4-month and 10-month post-activation follow-up. **Hypotheses:** This objective was to provide an accurate estimate of the SADE rate and device failure and replacement rate associated with the Esteem® System. Therefore, no formal hypothesis tests were conducted. PMA P090018: FDA Summary of Safety and Effectiveness Data page 19 {19} ## Adjudication of Adverse Events, SADEs, and Device Failures: Adverse Events were collected throughout the Pivotal Trial. Envoy Medical established a Clinical Events Committee (CEC) that adjudicated clinical adverse events for the Esteem clinical trial. The CEC was responsible for establishing and approving decision rules and definitions for the determination of clinical adverse events using data collected on Case Report Forms (CRF’s) in the trial. The CEC reviewed all AEs and classified each event as serious or not serious and as device related, procedure related, pre-existing, or not related. The members of the CEC are physicians/PhDs drawn from the Ear, Nose &amp; Throat (ENT) medical community. The CEC is made up of three voting members. At the time of review, there were two otolaryngology surgeons and one audiologist on the CEC. A representative from Envoy Medical chaired the committee meetings, but Envoy Medical states that the CEC chair did not vote during adjudication of AEs. ## Definitions The protocol used the following definitions of various categories of Adverse Events. ### Adverse Event (AE) An Adverse Event is any undesirable clinical event occurring to a subject, during a clinical trial, whether or not it is considered related to the investigational product. This includes a change in a subject’s condition or laboratory results, which has or could have a deleterious effect on the subject’s health or well being. ### Adverse Device Effect (ADE): An Adverse Device Effect is an Adverse Event related to the investigational device. ### Unanticipated Adverse Device Effects (UADE) An Unanticipated Adverse Device Effect is any serious adverse effect on health or safety or any life threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects. ### Serious Adverse Event (SAE) or Severe Adverse Device Effect (SADE) A Serious Adverse Event (SAE) or Serious Adverse Device Effect (SADE), are events which: PMA P090018: FDA Summary of Safety and Effectiveness Data page 20 {20} - Result in death - Is life threatening - Requires inpatient hospitalization - Results in persistent or significant disability/incapacity - Is a congenital anomaly/birth defect - Requires intervention to prevent permanent impairment/damage ## Co-Primary Safety Objective – Cochlear Stability To demonstrate that the subjects' cochlear function remains unchanged with the Esteem® System as shown by comparison of the subjects' pre-implant baseline bone conduction threshold (BCT) versus the subjects' 4-month and 10-month post-activation BCT. *Endpoint Analysis:* Average and individual changes were evaluated per the protocol. Bone conduction was measured with forehead probe placement. Stability was defined as bone conduction threshold change to be within ± 10 dB. *Note:* A Safety Algorithm was adopted to measure cochlear stability for any bone conduction results outside the stability range. This Safety Algorithm can be located in Appendix 1 (Section X) below. ## Co-Primary Primary Effectiveness Objective – Speech Reception Threshold To demonstrate that the Esteem® System improves the speech reception threshold of sensitivity for hearing and identifying speech signals as well as or better than the pre-implant hearing aid (aided condition). *Endpoint:* Comparison of the speech reception threshold (SRT) using the Esteem® System (4 months post activation) as compared to the pre-implant aided condition. *Hypothesis:* The 95% Lower Confidence Bound (LBC) for the mean of difference between the SRT at baseline versus four months is greater than or equal to -5 dB. $$95\% \text{ LCB for Mean(Pre-implant aided} - \mu 4 \text{ month}) \geq -5$$ ## Co-Primary Effectiveness Objective – Word Recognition Scores To demonstrate that the Esteem® System at the 4 months postactivation visit is as effective as or better than the hearing aid for improving speech discrimination (intelligibility) as shown by the word recognition score at 50 dB HL. PMA P090018: FDA Summary of Safety and Effectiveness Data page 21 {21} Endpoint: Comparison of the word recognition score (WRS) using the Esteem® System at 4 months post-activation compared to the pre-implant aided condition. Hypothesis: This objective was to provide a comparison of the WRS at 50 dB HL associated with the Esteem® System versus the baseline aided condition. There is no formal hypothesis and descriptive statistics are to be presented. Statistical Analysis: The Word Recognition Scores will be compared using the Thornton and Raffin (1978) published upper and lower limits for various word lists based upon percentage scores. An analysis showing the “% better than”, “% equal to”, and “% below” the aided condition (HA) will be presented. Reference: Thornton AR, Raffin MJ. Speech discrimination scores modeled as a binomial variable. J Speech Hear Res 1978; 21:507-18. ## Secondary Effectiveness Objectives No hypothesis testing was pre-specified for any of the secondary endpoints in the protocol. ## Pure Tone Average (PTA) To demonstrate that the Esteem® System at the 4 month post activation visit improves the 3-frequency (500, 1000, and 2000 Hz) pure tone average (PTA) when compared to the baseline unaided condition. ## QuickSIN To demonstrate that the Esteem® System at the 4 month postactivation visit is as effective as or better than the hearing aid for improving speech discrimination (intelligibility) as shown by the QuickSIN (speech in noise) test results. ## APHAB Quality of Life (QOL) To show that the Esteem® System improves Quality-of-Life when compared to the baseline aided condition as shown by APHAB scores. ## Esteem Questionnaire Quality of Life (QOL) To gather subject feedback and comments on the use of the Esteem® System relative to the pre-implant hearing aid (aided condition) as shown by the Esteem® Questionnaire. PMA P090018: FDA Summary of Safety and Effectiveness Data page 22 {22} # B. Accountability of PMA Cohort For the pivotal study (G070162), 57 of 60 enrolled subjects were successfully implanted with the study device at three study sites: 22 subjects at Southeastern ENT &amp; Sinus Center in Greensboro, NC; 18 subjects at Shohet Ear Associates Medical Group in Newport Beach, CA; and 17 subjects at Lahey Clinic in Burlington, MA (Table III). Among the 57 implanted subjects, 54 subjects completed the 4-month follow-up (3 subjects had revision surgery due to limited benefit and were excluded from the analysis of the primary and secondary effectiveness outcomes) and 52 subjects completed the 10-month follow-up. Of the 60 enrolled subjects, three were not implanted. Two patients were enrolled, underwent surgery, but did not receive the implant because the middle ear space was inadequate. A third subject decided to withdraw from the study after signing the consent form. Of the 57 implanted subjects, three did not make the 4-month follow-up because of revision surgery. Of the 54 subjects who reached the 4-month follow-up, two subjects did not reach the 10-month follow-up. The first of these subjects was explanted due to an incision breakdown that would not heal (possibly related to a smoking habit). A second subject had not been scheduled for the 10-month follow-up at the time the data base was finalized. Table III. Patient Accountability by Site and Follow-Up Visit. | | Total Implanted | 4-month Follow-Up N (%) | 10-month Follow-Up N (%) | | --- | --- | --- | --- | | All | 57 | 54 (94.7) | 52 (91.2) | | Southeastern ENT & Sinus Center | 22 | 21 (95.5) | 21 (95.5) | | Shohet Ear Associates Medical Group | 18 | 18 (100.0) | 16 (88.9) | | Lahey Clinic | 17 | 15 (88.2) | 15 (88.2) | # C. Study Population Demographics and Baseline Parameters The subject demographic data is summarized in Table IV. The subjects' average age was 52.9 years, ranging from 18 to 77 years; 67% (38) were male and 33% (19) were female. Fifty six (56) of the 57 implanted subjects with available baseline data were Caucasian (98%), and one subject was Asian. At the time of study enrollment 25% (14) were retired, 9% (5) worked part time, and 51% (29) worked full time. Fifty four PMA P090018: FDA Summary of Safety and Effectiveness Data {23} (54) of the 57 subjects (95%) suffered a gradual hearing loss that was diagnosed at an average age of 32.5 years, ranging from 1 to 66 years. The degree of hearing loss, based on pure tone average (PTA), was mild in 3 subjects, moderate in 44 subjects and severe in 10 subjects (Table IV). All 57 (100%) subjects were current users of a hearing aid with average usage time of 13.7 years, ranging from 0.4 to 37.8 years. Of the subjects implanted, 49 (86%) subjects used hearing aids in both ears. Table IV. Subject Demographics and Degree of Hearing Loss. | Demographics | Mean ± SD^{°}n (min, max) | Degree of Hearing Loss (implanted ear) | N/Total (%) | | --- | --- | --- | --- | | Age (years) | 52.9 ± 15.8 | Mild (PTA ≤ 40 dB) | 3/57 (5.3%) | | | 57 (18.0, 77.2) | Moderate (41 dB < PTA ≤ 55 dB) | 25/57 (43.8%) | | | N/Total (%) | Moderate Severe (56 dB < PTA ≤ 70 dB) | 15/57 (26.3%) | | Gender | | Severe (PTA > 71 dB) | 10/57 (17.6%) | | Male | 38/57 (66.7%) | | | | Female | 19/57 (33.3%) | | | | Race/Ethnicity | | | | | White/Caucasian | 56/57 (98.2%) | | | | Black/Non-Hispanic | 0/57 (0%) | | | | Hispanic | 0/57 (0%) | | | | Asian | 1/57 (1.8%) | | | | Work Status | | | | | Full Time Employee | 29/57 (50.9%) | | | | Part Time Employee | 5/57 (8.8%) | | | | Retired | 14/57 (24.6%) | | | | Unemployed | 4/57 (7.0%) | | | | Other | 5/57 (8.8%) | | | ## D. Safety and Effectiveness Results ### 1. Safety Results The analysis of safety was based on the cohort of 60 subjects. The key safety outcomes for this study are presented below in Tables V to XIV and Figure 2. Adverse effects are reported in Tables V, VI, IX, XI-XIII, and Figure 2. PMA P090018: FDA Summary of Safety and Effectiveness Data {24} PMA P090018: FDA Summary of Safety and Effectiveness Data page 25 30 # Adverse effects that occurred in the PMA clinical study: ## Severe Adverse Device Effect (SADE) The CEC determined that there were 6 SADEs reported in 6 subjects, for an incidence of 10.5% (6/57), as shown in Table V. Among the SADEs, three were due to limited benefit which resulted in revision procedures. One subject had incision site infection. One other subject had incision breakdown. The sixth subject experienced severe pain and facial weakness which resolved with medication. Table V. Severe Adverse Device Effects (SADEs). Co-Primary Safety Endpoint. | Subject # | Event | Total Number | Intervention | Status | | --- | --- | --- | --- | --- | | 103-24 MIEKU | Severe pain and Facial Weakness | 1 | Medication | Resolved | | 109-34 CHWYA | Incision Site Infection | 1 | Medication | Resolved | | 103-22 JELGR 102-22 DAAKU 109-24 CRBAR | Limited Benefit | 3 | Revision Procedures with replacement of parts of the Device | 1 Subject has reached 4 month Endpoint, Remaining 2 Subjects have reached 2 month post-operative period, but not the 4 month Endpoint at the time of this report | | 105-37 LADGO | Incision Breakdown | 1 | Required Explantation | Reconstructed with Incudoplasty | | Total SADE Events | | 6 | | | For more detail concerning the 3 patients with Limited Benefit and 1 patient who required explantation, refer to Table VI. {25} Table VI. Device Failure/Revisions/Explants and Reconstruction. | Subject # | Event | Implant Date | Elapsed time to resolution | Revision/Explant Date | Findings at Surgery | Reimplant /Reconstruction Method | | --- | --- | --- | --- | --- | --- | --- | | 103-22 JELGR | Limited Benefit shortly after Activation | 1/30/08 | 8.5 months | 10/16/08 | Fibrous Adhesions fixing sensor to incus and Driver **Additional observation:** MedCem butted against the short process of incus causing lower than expected Sensor and ISA test performance at implant. | Replaced Sound Processor and Sensor | | 109-22 DAAKU | Limited Benefit at Activation | 5/16/08 | 12.5 months | 5/29/09 | Extensive Fibrous adhesions in the facial recess surrounding the Driver and stapes. **Additional observation:** An unusually small amount of EnvoyCem was present to form the Driver to Stapes connection. | Replaced Sound Processor and Driver | | 109-24 CRBAR | Limited Benefit. | 5/30/08 | 11 months | 5/01/09 | Extensive Fibrous adhesions noted in the facial recess surrounding the Driver and stapes. **Additional findings:** Driver tip pulled away from stapes & unusually small amount EnvoyCem | Replaced Sound processor and Driver | | 105-37 LAGDO | Repeated Incision breakdown | 6/27/08 | 8months | 2/27/09 | Incision had a large opening under the scab | Reconstructed with Incudoplasty | PMA P090018: FDA Summary of Safety and Effectiveness Data {26} # Device Failure Summary A failure summary was presented by the applicant for 3 subjects that received Limited Benefit from the device as follows: Subject 103-22 JELGR reported a decrease in benefit shortly after Activation, continuing through the 2-month follow-up visit. Diagnostic testing indicated that the Sensor output was lower than normal. The revision procedure found extensive dense fibrous adhesions filling the facial recess. The fibrous adhesions had fixed the Sensor to the incus and the Driver to the malleus. In order to remove the fibrous adhesions, the surgeon had to remove the Sensor and Driver and replace them with new components. During this process, surgeon noticed some MedCem butted against the short process of the incus, restricting its movement. He removed this obstruction in order to restore mobility of the incus. The new Sensor, Driver and System tests were conducted with acceptable results. The surgeon’s conclusion was that the dense fibrous adhesions that formed after implant prevented the Sensor and incus from moving properly causing the poor performance. The MedCem attached to the incus likely was the cause of lower than expected Sensor and System ISA test performance at implant but as indicated by the data the fibrous adhesions that developed after Activation were the cause of the decrease in benefit. Subject 109-24 CRBAR reported limited benefit at Activation that progressively worsened through the 2-month follow-up. Diagnostic testing indicated that the Driver output was lower than normal. The revision procedure showed extensive fibrous adhesions in the facial recess surrounding the Driver and stapes. The Sensor was functioning properly and not affected by the adhesions. During removal of the fibrotic tissue, The surgeon found that the Driver tip had been laterally pulled away from the stapes EnvoyCem connection and that an unusually small amount of EnvoyCem was present to form the Driver-stapes connection. This subject had a small facial recess opening that could have affected visibility and the original application of EnvoyCem. The surgeon implanted a new Driver and used EnvoyCem to complete the connection to the stapes. The new Driver, Sensor and System tests were conducted with acceptable results. The conclusion was that the fibrous adhesions that formed after implant likely prevented the Driver and stapes from functioning properly causing the limited benefit. PMA P090018: FDA Summary of Safety and Effectiveness Data page 27 32 {27} Subject 109-22 DAKKU reported limited benefit at Activation that progressively worsened through the 2-month follow-up. Diagnostic testing indicated that the Driver output was lower than normal. The revision procedure showed extensive fibrous adhesions in the facial recess surrounding the Driver and stapes. The Sensor was functioning properly and not affected by the adhesions. During removal of the fibrotic tissue, the surgeon found that an unusually small amount of EnvoyCem was present to form the Driver-stapes connection. This subject had a small facial recess opening that could have affected visibility and the original application of EnvoyCem. The surgeon implanted a new Driver and used EnvoyCem to complete the connection to the stapes. The new Driver, Sensor and System tests were conducted with acceptable results. The conclusion was that the fibrous adhesions that formed after implant likely prevented the Driver and stapes from functioning properly causing the limited benefit. ## Bone Conduction Threshold - Cochlear Stability The objective was to demonstrate that the subject’s cochlear function remains unchanged with the Esteem® System as shown by comparison of the subject’s pre-implant baseline Bone Conduction Threshold (BCT) vs. the subject’s 4-month and 10-month post-activation BCT. Average and individual changes were evaluated per the protocol. Bone conduction was measured with forehead probe placement. Stable results should be within ± 10 dB. A Safety Algorithm (Appendix 2) was adopted to measure cochlear stability for any bone conduction results outside the stability range. At the group level, changes in bone conduction threshold were used to determine whether the Esteem® System caused damage to residual cochlear function. The average 3-frequency (500, 1000, 2000 Hz) bone conduction change from baseline for all subjects was 0.1 ± 0.9 dB (mean ± standard error) at 4 months and -0.8 ± 1.1 dB (mean ± standard error) at 10 months (Table VII). This small change is indicative of no systemic cochlear damage being caused by either the implant or the therapy. PMA P090018: FDA Summary of Safety and Effectiveness Data page 28 33 {28} Table VII. Average Bone Conduction Threshold Results (reported as mean +/- standard error). | | 500 Hz mean ± se (CI range) | 1000 Hz mean ± se (CI range) | 2000 Hz mean ± se (CI range) | 4000 Hz mean ± se (CI range) | PTA mean ± se (CI range) | | --- | --- | --- | --- | --- | --- | | Pre- Implant | 45.0±1.9 (41.3, 48.7) | 57.5±1.7 (54.1, 60.8) | 66.6±1.4 (63.7, 69.4) | 65.0±1.7 (61.5, 68.5) | 56.3±1.3 (53.7, 58.9) | | 4-Month | 45.4±1.9 (41.7, 49.1) | 57.9±1.6 (54.6, 61.1) | 67.4±1.3 (64.8, 70.0) | 65.6±1.5 (62.6, 68.6) | 56.4±1.3 (53.7, 59.0) | | Mean Difference | 0.0 ± 0.9 (-1.8, 1.8) | 0.0 ± 1.0 (-2.0, 2.0) | 2.2 ± 1.3 (-0.4, 4.8) | 1.2 ± 1.2 (-1.3, 3.7) | 0.1 ± 0.9 (-1.7, 2.0) | | 10-Month | 42.6±2.0 (38.7, 46.5) | 56.9±1.6 (53.8, 60.1) | 68.0±1.4 (65.2, 70.7) | 66.3±1.5 (63.4, 69.3) | 55.3±1.5 (52.3, 58.3) | | Mean Difference | -2.3±1.0 (-4.4, -0.3) | -0.3±1.2 (-2.7, 2.0) | 1.3±1.4 (-1.5, 4.1) | 2.2±1.3 (-0.5, 4.8) | -0.8±1.1 (-3.1, 1.5) | There was no mean change in bone conduction threshold at 4-months relative to the baseline for frequencies 500 and 1000 Hz (0.0 ± 6.4 dB, 0.0 ± 7.0 dB, respectively; mean ± standard deviation). There were slight increases in the bone conduction threshold for frequencies 2000 and 4000 Hz (2.2 ± 7.8 dB, and 1.2 ± 7.6 dB, respectively; mean ± standard deviation). At the individual level, all subjects with 4-month and 10-month data in the database as of July 27, 2009, were analyzed according to the change criteria adopted in bone conduction (BC) and safety algorithm (SA) in accordance with the clinical protocol (i.e., 2 out of 4 frequencies change greater than 10 dB or 1 frequency greater than 20 dB; for details, see Appendix 2). Out of 54 subjects who had 4-month follow-up, the BC/SA threshold could not be determined in two subjects (0204-103-34-CYJTA and 0204-109-27-BRTGR) at one or more frequencies due to equipment limits. For the remaining 52 subjects, no subjects had a BC/SA threshold shift at the 4-month endpoint greater than the protocol criteria. At 10 months, the applicant reported that 52 subjects had the BC/SA data. The BC/SA threshold could not be determined at one or more frequencies in one subject (0204-109-27-BRTGR) due to equipment limits. Of the 51 subjects, one subject (0204-103-28-TOSTR) had a BC/SA threshold shift of greater than 20 dB at 4000 Hz. The more consistent and stable bone conduction measurements in G070162 compared to G000321 may be due to the forehead probe placement versus the mastoid probe placement. Bone conduction was shown to be stable through the 4- and 10-month intervals. PMA P090018: FDA Summary of Safety and Effectiveness Data page 29 34 {29} In a worst-case scenario under the intent to treat population, 13% (8 out of 60) and 15% (9 out of 60) of the study cohort does not meet this safety objective at 4- and 10-month follow-up, respectively. At the 10-month follow-up, one subject (103-28) had a BC/SA threshold shift greater than the protocol criteria at the 4000 Hz. A summary of clinical safety outcomes is provided in Table VIII. Table VIII. Summary of Clinical Safety Data. | Clinical Protocol Objectives | 4-Month Results | 10-Month Results | | --- | --- | --- | | Primary Safety Objective: • Serious Adverse Device Effects (SADE) • Incidence of Device Failures and Replacements | SADE • Three (3) subjects for facial weakness / incision issues • Three (3) subjects for revision procedures to date • SADE rate: 10.5% (6 of 57) Failures • Three (3) failures resulting in approved revisions were reported in three unique subjects prior to the 4-month follow-up • Failure rate: 5.3% (3 of 57) | SADE • No additional SADE were reported between the 4-month and 10-month follow-up visits Failures • No additional failures were reported between the 4-month and 10-month follow-up visits | | Primary Safety Objective: • Bone conduction (BC) threshold at 4 months post-activation vs. pre-implant • Safety Algorithm (SA) for those that fail BC | Bone Conduction • Average 3 frequency (500, 1K, 2K) bone conduction change of 0.1 dB at 4 months vs. pre-implant. • Individually, no subjects (0) at 4 months had BC/SA change per the protocol criteria from pre-implant. | Bone Conduction • Average 3 frequency (500, 1K, 2K) bone conduction change of -0.8 dB at 10 months vs. pre-implant. • Individually, one subject (1) at 10 months had BC/SA change per the protocol criteria from pre-implant at 4 kHz. | ## Adverse Event Results The list of reported adverse events related to the device as determined by the CEC are shown in Table IX (as provided by the applicant in the PMA): - 96 ADEs were reported in Table IX if they were found during CEC adjudication to be not serious and were found to be caused by the mastoidectomy w/facial recess, device, peri-operative surgery related, or device implant procedure related. - The majority of these Adverse Effects were classified as mild or moderate. - 70% of the ADEs have resolved. - The remaining 30% of the ADEs are ongoing for over a year at the time of this report. Ongoing ADEs include conditions like taste disturbance, facial weakness/paralysis, tinnitus, dizziness, middle ear effusion, and ear pain. PMA P090018: FDA Summary of Safety and Effectiveness Data {30} The list of reported adverse events that are not device related as determined by the CEC are shown in Table X: - Events were classified as AE's if they were found during CEC adjudication to be caused by underlying or concomitant illness, concomitant medications, or other causes. - Seventeen events were classified as mild, 4 as moderate, and 1 as severe. - Of the 29 AEs reported, 21 (72%) have resolved. - 8/29 AEs (28%) were still ongoing at the time of this report. Table IX. CEC-adjudicated Adverse Device Effects (96 Events in 43 Subjects). | Event | Mild | Moderate | Severe | Total | | --- | --- | --- | --- | --- | | Aural Fullness | 2 | 0 | 0 | 2 | | Blistering TM | 1 | 0 | 0 | 1 | | Chest Pain | 1 | 0 | 0 | 1 | | Discomfort above Incision | 1 | 1 | 0 | 2 | | Dizziness | 1 | 0 | 0 | 1 | | Dry Eye | 1 | 0 | 0 | 1 | | Disequilibrium | 3 | 0 | 0 | 3 | | Ear Cracking | 2 | 0 | 0 | 2 | | Ear Pain | 4 | 0 | 0 | 4 | | Ear Roaring | 1 | 0 | 0 | 1 | | Eye Irritation | 1 | 0 | 0 | 1 | | Eye Squint | 1 | 0 | 0 | 1 | | Facial Weakness/Paralysis | 2 | 1 | 0 | 3 | | Feedback | 1 | 0 | 0 | 1 | | Fluid | 3 | 6 | 0 | 9 | | Headache | 1 | 1 | 0 | 2 | | Imbalance | 1 | 0 | 0 | 1 | | Incision Discomfort | 3 | 0 | 0 | 3 | | Incision Drainage | 1 | 0 | 0 | 1 | | Limited Benefit | 1 | 0 | 0 | 1 | | Metallic Taste | 1 | 0 | 0 | 1 | | Middle Ear Effusion | 8 | 0 | 0 | 8 | | Moist Debris | 1 | 0 | 0 | 1 | | Nasal Drainage | 1 | 0 | 0 | 1 | | Noise | 1 | 0 | 0 | 1 | | Numbness | 1 | 0 | 0 | 1 | | Otitis Externa | 2 | 0 | 0 | 2 | | Otalgia | 2 | 0 | 0 | 2 | | Pain | 2 | 0 | 0 | 2 | | Taste Disturbance | 23 | 1 | 0 | 24 | | Tinnitus | 8 | 0 | 0 | 8 | | TM Perforation | 1 | 0 | 0 | 1 | | Tongue Numbness | 1 | 0 | 0 | 1 | | Unsteadiness | 1 | 0 | 0 | 1 | | Vertigo | 0 | 1 | 0 | 1 | | TOTAL | 85 | 11 | 0 | 96 | PMA P090018: FDA Summary of Safety and Effectiveness Data {31} PMA P090018: FDA Summary of Safety and Effectiveness Data page 32 37 Table X. CEC-Adjudicated Adverse Events (29 Events in 25 subjects). | Event | Mild | Moderate | Severe | Total | | --- | --- | --- | --- | --- | | Apnea | 1 | 0 | 0 | 1 | | Dizziness | 1 | 0 | 0 | 1 | | Ear Canal Wound (non-implant ear) | 0 | 0 | 1 | 1 | | Eustachian Tube Dysfunction | 1 | 0 | 0 | 1 | | Headache | 1 | 0 | 0 | 1 | | Imbalance | 1 | 0 | 0 | 1 | | Knee Pain | 1 | 0 | 0 | 1 | | Light Headedness | 1 | 0 | 0 | 1 | | ME Effusion | 1 | 0 | 0 | 1 | | ME Fluid | 1 | 0 | 0 | 1 | | Motor Vehicle Accident | 1 | 0 | 0 | 1 | | Mucosal Inflammation | 0 | 1 | 0 | 1 | | Nose bleed | 2 | 0 | 0 | 2 | | Pain | 0 | 1 | 0 | 1 | | Post Nasal Drainage | 1 | 0 | 0 | 1 | | Rapid Heart Rate | 1 | 0 | 0 | 1 | | Rash Abdominal | 1 | 0 | 0 | 1 | | Root Canal | 1 | 0 | 0 | 1 | | Sinus Infection | 2 | 0 | 0 | 2 | | Sprained Ankle | 0 | 1 | 0 | 1 | | Touch Sensation | 1 | 0 | 0 | 1 | | Tinnitus | 0 | 1 | 0 | 1 | | URI | 2 | 0 | 0 | 2 | | Vertigo | 2 | 0 | 0 | 2 | | Yeast infection | 1 | 0 | 0 | 1 | | TOTAL | 24 | 4 | 1 | 20 | Table XI, Table XII, Table XIII, and Figure 2 have been compiled by FDA from a spreadsheet provided by the applicant which includes all adverse events. All events have been grouped into 9 broad categories of Taste, Middle Ear Effusion, Pain, Tinnitus, Imbalance/Dizziness, Facial Paresis, Limited Benefit, Headache, and Miscellaneous. Table XII summarizes all 133 adverse events observed during this study and subject status at the time of this PMA submission. Table XII presents a detailed description of the adverse events in each of the 9 categories. The following observations can be made from these two tables: - Of the 133 adverse events, 78% have resolved, 21% remain unresolved, and the status of 1 event is unknown. - The most frequent adverse event was taste disturbance (24 of 57 subjects, 42%). This adverse event has not resolved for 8 subjects (14%). - Facial paresis/paralysis was reported in 7% of subjects with 1% still reported to be ongoing after one year. {32} - 52 (91%) of 57 subjects experienced AEs; 36 of 52 Subjects experienced multiple (2-8) AEs, not all events are resolved; 26 Subjects have ongoing AEs. Table XI. Categories of Adverse Events and Status. | Adverse Event (AE) Categories | Number of AEs (% of total AEs) | Number of Subjects with AEs (% of 57 implanted subjects) | Number of Resolved AEs (% of category) | Number of Subjects with Resolved AEs (% of 57 implanted subjects) | Number of AEs Ongoing (% of category) | Number of Subjects with Ongoing AEs (% of 57 implanted subjects) | Number of AEs with Resolution Status Unknown (% of category) | Number of Subjects with Resolution Status Unknown (% of 57 implanted subjects) | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Taste Disturbance | 25 (19%) | 24 (42)% | 16 (64%) | 15 (26%) | 8 (32%) | 8 (14%) | 1 (4%) | 1 (2%) | | Middle Ear Effusion | 18 (14%) | 18 (32%) | 18 (100%) | 18 (32%) | 0 | 0 | 0 | 0 | | Pain | 12 (9%) | 12 (21%) | 8 (67%) | 8 (14%) | 4 (33%) | 4 (7%) | 0 | 0 | | Imbalance/Vertigo/Dizziness | 11 (8%) | 11 (19%) | 9 (82%) | 9 (16%) | 2 (18%) | 2 (4%) | 0 | 0 | | Tinnitus | 10 (8%) | 10 (18%) | 7 (70%) | 7 (12%) | 3 (30%) | 3 (5%) | 0 | 0 | | Facial Paresis/Paralysis | 4 (3%) | 4 (7%) | 2 (50%) | 2 (4%) | 2 (50%) | 2 (4%) | 0 | 0 | | Mild/Moderate | 4 (3%) | 4 (7%) | 4 (100%)* | 4 (7%) | 0 | 0 | 0 | 0 | | Headaches | 3 (2%) | 3 (5%) | 3 (100%) | 3 (5%) | 0 | 0 | 0 | 0 | | Miscellaneous | 46 (34%) | 30 (52%) | 37 (80%) | ** | 9 (20%) | ** | 0 | 0 | | Total | 133 (100%) | 52 (91)% | 104(78%) | *** | 28 (21%) | *** | 1 (.008%) | 1 (2%) | *1 Subject resolved without intervention, 1 Subject has reached the 4 month Endpoint; 2 Subjects have only reached 2 month post-operative period, but not the 4 month Endpoint at the time of this report. ** 12 of 30 Subjects (40%) experienced 2-4 AEs in Miscellaneous category, not all events resolved; 12 Subjects have ongoing AEs *** 36 of 52 Subjects experienced 2-8 AEs, not all events resolved; 26 Subjects have ongoing AEs PMA P090018: FDA Summary of Safety and Effectiveness Data page 33 38 {33} Table XII. Description of Adverse Events with Categories. | Adverse Event Category | Description of Adverse Event | Number of Events | | --- | --- | --- | | Taste Disturbance | | 25 | | | Taste Disturbance | 18 | | | Metallic Taste | 3 | | | Altered Taste | 1 | | | Disturbed Taste | 1 | | | Taste Disturbance | 1 | | | Taste Disturbance (Delayed Onset) | 1 | | Middle Ear Effusion | | 18 | | | Middle Ear Fluid | 5 | | | Effusion | 3 | | | Fluid Behind TM | 2 | | | Crackling Sound | 1 | | | Crackling Drainage Sound | 1 | | | Effusion ( R ) | 1 | | | Fluid AS | 1 | | | Middle Ear Effusion | 1 | | | Middle Ear Fluid | 1 | | | Middle Ear Effusion , Rt. Ear, Implant Ear | 1 | | | Residual Effusion L Middle Ear | 1 | | Pain | | 12 | | | Otalgia | 2 | | | Discomfort Above Implant | 1 | | | Discomfort/Pain R Side of Head | 1 | | | Ear Canal Pain | 1 | | | Ear Pain | 1 | | | Ear Pain/Pressure | 1 | | | Intermittent Otalgia | 1 | | | L Ear Pain | 1 | | | Pain Around Incision | 1 | | | Pain in Temporal Region /Cheek | 1 | | | Pain/Incision discomfort | 1 | | Vertigo/Dizziness/Imbalance | | 11 | | | Vertigo | 3 | | | Dysequilibrium | 2 | | | Imbalance | 1 | | | Mild Dysequilibrium | 1 | | | Unsteadiness | 1 | | | Unsteadiness | 1 | | | Dizziness | 2 | | Tinnitus | | 10 | | | Tinnitus Left Ear | 2 | | | Right Ear Roaring | 1 | | | Slight Increase in Tinnitus | 1 | | | Tinnitus Left Ear | 1 | | | Tinnitus | 5 | | Facial Paresis | | 4 | PMA P090018: FDA Summary of Safety and Effectiveness Data {34} | | Facial Palsy L Facial Paresis Facial Weakness R Facial Weakness | 1 1 1 1 | | --- | --- | --- | | Limited Benefit | | 4 | | | Limited Benefit * Limited Benefit ** Limited Benefit ** Limited Benefit ** | 1 1 1 1 | | Headaches | | 3 | | | Headache Headache Frontal Headache | 1 1 1 | | Miscellaneous | | 46 | | | Aural Fullness Nose Bleed Sinus Infection Motor Boat Sound/Shorting Out of Sound URI Ankle Trouble/Broken leg Apnea (pre-existing) Incision Breakdown (1), Infection(2), and Discomfort (1) Nasal Drainage/Post Nasal Drip TM Perforation/TM Blistering Otitis Externa (1), Debris in Ear Canal (2), and Sore in Ear Canal (1) Eustachian Tube Dysfunction/Feedback TIA, Chest Pain, Knee Pain, Pregnancy, MVA Rapid Heart Beat, Rash, Tooth Pain Yeast Infection, Discomfort, Light Headedness Hair Follicle Incision and Blood Fluid (L) Dry Eye, Eye Irritation, Eye Squint Numbness, Numbness of left Tongue, Numbness of Tongue | 2 2 2 2 (1 each) 2 2 (1 each) 1 4 2 (1 each) 2 (1 each) 4 2 (1 each) 5 (1 each) 3 (1 each) 3 (1 each) 2 (1 each) 3 (1 each) 3 (1 each) | | Grand Total | | 133 | * One Subject with Limited Benefit improved without intervention ** Three Subjects with Limited Benefit underwent revision surgery Figure 2 represents the breakdown of adverse events by each of the three sites. Table XIII verifies that Site 109 has very few ongoing Adverse Events as compared to Site 103 and 105. Figure 2 and Table XIII show that there is wide variability of reported Adverse Events across the three sites that participated in this study. PMA P090018: FDA Summary of Safety and Effectiveness Data {35} Table XIII. Status of Adverse Events by Clinical Site. | Adverse Events | Site 103 | Site 105 | Site 109 | Grand Total | | --- | --- | --- | --- | --- | | | | | | | | Not Resolved, No Follow Up Necessary | | 1 | | 1 | | Ongoing at the Time of Report | 15 | 19 | 3 | 37 | | Recovered, No Residual Effects | 35 | 45 | 14 | 94 | | Unknown | | 1 | | 1 | | Grand Total | 50 | 66 | 17 | 133 | | | | | | | | Number of Subjects Implanted | N=22 | N=18 | N=17 | N=57 | ![img-1.jpeg](img-1.jpeg) Figure 2. Numbers of adverse events grouped by category and site. ## Unanticipated Adverse Device Effect (UADE) The Clinical Events Committee (CEC) determined that there were no UADEs reported during this trial. PMA P090018: FDA Summary of Safety and Effectiveness Data {36} # Severe Adverse Events (SAE) A total of two events have been reported which were classified as SAEs: - Broken leg (recovered) - Transient ischemic attack (recovered) ## 2. Effectiveness Results ### Speech Reception Threshold (SRT) The criterion used is that the 95% Lower Confidence Bound (LBC) for the mean of difference between the SRT at baseline versus four months is greater than or equal to -5 dB. The mean SRT decrease at 4 months from baseline (pre-implant, aided) was 10.6 with a 95% confidence interval ranging from 7.1 to 14.2 (Table XIV). Table XIV. Mean Improvement in SRT Scores at 4 and 10 Months (Unadjusted). | Follow-up Period | SRT (in dB) mean ± se n (min, max) | | | | --- | --- | --- | --- | | | Pre-Implant Aided | 4-Month | 10-Month | | | 41.2 ± 1.5 57 (38.3, 44.1) | 30.6 ± 1.6 54 (27.4, 33.7) | 29.4 ± 1.6 52 (26.1, 32.7) | | Mean Improvement (95% CI) | NA | 10.6 ± 1.8 (7.1, 14.2) | 11.4 ± 1.8 (7.7, 15.2) | However, as shown in Table XV the heterogeneity in the treatment effect among sites is statistically significant (p-value &lt; 0.01). Overall, the mean SRT improvement with the Esteem® compared to the preimplant hearing aid was 10.6 dB with the site-specific mean improvement between 1.3-16.9 dB. Table XV. Mean Speech Reception Threshold (SRT) Decrease at 4-Months Relative to the Baseline (Aided Condition) for the Three Investigational Sites. | Analysis | Site 103 Mean±SE | Site 105 Mean±SE | Site 109 Mean±SE | P-value for Site Differences | | --- | --- | --- | --- | --- | | Unadjusted | 11.9±2.6 | 16.9±2.8 | 1.3±3.0 | <0.01 | PMA P090018: FDA Summary of Safety and Effectiveness Data page 37 {37} # Word Recognition Score The applicant's objective was to demonstrate that the Esteem® at the 4 months post-activation visit is as effective as or better than the hearing aid for improving speech discrimination (intelligibility) as shown by the word recognition score at 50 dB HL. The endpoint was the comparison of the word recognition score (WRS) using the Esteem® at 4 months post-activation compared to the pre-implant baseline aided condition. The applicant indicated that the objective of WRS was to provide a comparison of the Word Recognition Scores at 50 dB HL associated with the Esteem versus the baseline aided condition. The applicant did not propose any formal hypothesis, and the WRS was analyzed using the method described by Thornton and Raffin (Speech discrimination scores modeled as a binomial variable; J Speech Hear Res 1978; 21:507-18) regarding upper and lower limits for various word lists based upon percentage scores. An analysis showing the “% better than”, “% equal to”, and “% below” the pre-implant baseline aided condition was presented. As reported, Table XVI displays the WRS results at the 4- and 10-month intervals. At 4 months, 93% of the subjects’ WRS was as good as or better than that in the aided baseline condition (HA), and 7% exhibited below. The percentage of subjects having equivalent or better than HA decreased to 88% at 10 months, and those exhibiting below HA increased to 12%. Table XVI. Word Recognition Scores (WRS) at 50 dB HL. | | All Subjects | | | --- | --- | --- | | | 4 Month N=54 | 10 Month N=52 | | % Better HA | 30/54 (56%) | 32/52 (62%) | | % = HA | 20/54 (37%) | 14/52 (27%) | | % Below HA | 4/54 (7%) | 6/52 (12%) | The mean change in WRS at the 4-month visit was 21.7%, with a 95% confidence interval of 13.3 to 30.1 (Table XVII). However, as also observed in the SRT endpoint data, there is statistically significant heterogeneity in WRS among the sites (Table XVIII, $p=0.01$). The mean change in WRS at 4-months varied from 3.6 to 37.1 and at 10-months varied from 0 to 32.4, depending on the site. Table XVII. Mean Change in WRS at 4-Month Follow-Up. | Follow-up | Unadjusted Mean ± SE (95% CI) | | --- | --- | | 4 Months | 21.7 ± 4.2 (13.3, 30.1) | | 10 Months | 19.8 ± 4.3 (11.1, 28.4) | PMA P090018: FDA Summary of Safety and Effectiveness Data page 38 {38} Table XVIII. Word Recognition Score at 4-Months Compared to Baseline. | | Site 103 N (%) | Site 105 N (%) | Site 109 N (%) | | --- | --- | --- | --- | | Better HA | 11 (52.4) | 15 (83.3) | 4 (26.7) | | = HA | 9 (42.9) | 3 (16.7) | 8 (53.3) | | Below HA | 1 (4.8) | 0 (0.0) | 3 (20.0) | Overall, 93% of Esteem® recipients scored equal to or better than their pre-implant hearing aid. A summary of the WRS data found in Tables XVI and XVIII follows: - 7% scored less than their pre-implant hearing aid (0%-20% depending upon clinical site), - 37% scored equal to their pre-implant hearing aid (17%-53% depending upon clinical site), and - 56% scored better than their pre-implant hearing aid (27%-83% depending upon clinical site). ## Secondary Effectiveness Endpoint Analysis ### Pure Tone Average (PTA) The objective was to demonstrate that the Esteem System at the 4-month postactivation visit improves the 3-frequency (500, 1000, and 2000 Hz) pure tone average (PTA) when compared to the baseline unaided condition. For each subject, the 4-month, as well as the 10-month, air conduction data were compared to the baseline unaided data at various frequencies (Hz). Table XIX details the mean air conduction change and the number of subjects in each functional "benefit" group at each frequency. The data is also plotted in Figure 10. There were 96% (52/54) of subjects at the 4-month interval and 92% (48/52) at the 10-month interval who had PTA change greater than 10 dB. Table XIX. Air Conduction Threshold Change at 4…
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