**Implantable Middle Ear Hearing Device; Draft Guidance For Industry And
FDA**

***Draft Guidance -- Not for Implementation***

**This guidance document is being distributed for comment purposes
only.**

**Draft released for comment on \[release date as stated in FR
Notice\]**

![](media/image1.png){width="0.9631944444444445in"
height="1.0763888888888888in"}

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Devices and Radiological Health**

**Ear, Nose and Throat Devices Branch**

**Division of Ophthalmic and Ear, Nose, and Throat Devices**

**Office of Device Evaluation**

**Preface**

**Public Comment**

For 90 days following the date of publication in the Federal Register of
the notice announcing the availability of this guidance, comments and
suggestions regarding this document should be submitted to the Docket
No. assigned to that notice, Dockets Management Branch, Division of
Management Systems and Policy, Office of Human Resources and Management
Services, Food and Drug Administration, 5630 Fishers Lane, Room 1061,
(HFA-305), Rockville, MD 20852.

**Additional Copies**

Additional copies are available from the Internet at:
<http://www.fda.gov/cdrh/%5Bspecific> address\], or CDRH
Facts-On-Demand. In order to receive this document via your fax machine,
call the CDRH Facts-On-Demand system at 800-899-0381 or 301-827-0111
from a touch-tone telephone. Press 1 to enter the system. At the second
voice prompt, press 1 to order a document. Enter the document number
(**1406**) followed by the pound sign (#). Follow the remaining voice
prompts to complete your request.

**TABLE OF CONTENTS**

[1. INTRODUCTION 1](#introduction)

[2. DEVICE DESCRIPTION 2](#device-description)

[3. MANUFACTURING 3](#manufacturing)

[Software Validation 3](#software-validation)

[Sterilization 4](#sterilization)

[4. PRECLINICAL INFORMATION 5](#__RefHeading___Toc9070390)

[Design Characteristics of IMEHD 5](#design-characteristics-of-imehd)

[System Output and Response 5](#system-output-and-response)

[Biocompatibility 6](#biocompatibility)

[Animal Studies 6](#animal-studies)

[Environmental Testing 7](#environmental-testing)

[Electrical Testing 8](#electrical-testing)

[Stress, Fatigue, and Wear 9](#stress-fatigue-and-wear)

[Reliability 9](#reliability)

[5. INVESTIGATIONAL DEVICE EXEMPTIONS
10](#investigational-device-exemptions)

[Clinical Protocol 10](#clinical-protocol)

[6. CLINICAL RESULTS 14](#clinical-results)

[7. MODIFICATIONS TO APPROVED DEVICES
16](#modifications-to-approved-devices)

[APPENDIX A. INFORMED CONSENT 17](#appendix-a.-informed-consent)

[APPENDIX B. LABELING 18](#appendix-b.-labeling)

Implantable Middle Ear Hearing Device; Draft Guidance For Industry And
FDA

***This document is intended to provide guidance. It represents the
Agency's current thinking on this topic. It does not create or confer
any rights for or on any person and does not operate to bind the Food
and Drug Administration (FDA) or the public. An alternative approach may
be used if such approach satisfies the requirements of the applicable
statute and regulations.***

# INTRODUCTION

This guidance document is intended for manufacturers of implantable
middle ear hearing devices (IMEHD) for use in adults 18 years of age and
older. IMEHD require premarket approval applications (PMA). The product
code is MPV.

This guidance is based on current scientific knowledge, clinical
experience, and the recommendations made by the Ear, Nose, and Throat
Advisory Panel at the panel meeting held on June 18, 1999. This guidance
provides specific recommendations about IMEHD and is an adjunct to the
Code of Federal Regulations (CFR) such as 21 CFR Part 814-Premarket
Approval of Medical Devices, 21 CFR Part 801-Labeling, and other FDA
guidance documents for the preparation of premarket approval
applications, such as the **Premarket Approval Manual**,
[http://www.fda.gov/cdrh/dsma/pmaman/front.html]{.underline}. It does
not supersede those publications.

Wherever possible, you should follow the recommendations in this
guidance document and provide explanations of any deviations or
omissions in your PMA. PMAs that contain all the necessary information
recommended in this guidance ordinarily can be reviewed more
expeditiously than those that do not.

For the nonclinical laboratory studies, you should state whether each
nonclinical study of each final human prototype and the supporting
documentation is in compliance with Good Laboratory Practice for
Nonclinical Laboratory Studies, 21 CFR Part 58. If not, you should state
the reasons for noncompliance.

**The Least Burdensome Approach**

The issues identified in this guidance document represent those that we
believe need to be addressed before your device can be approved/cleared
for marketing. In developing the guidance, we carefully considered the
relevant statutory criteria for Agency decision-making. We also
considered the burden that may be incurred in your attempt to comply
with the guidance and address the issues we have identified. We believe
that we have considered the least burdensome approach to resolving the
issues presented in the guidance document. If, however, you believe that
information is being requested that is not relevant to the regulatory
decision for your pending application or that there is a less burdensome
way to address the issues, you should follow the procedures outlined in
the \"A Suggested Approach to Resolving Least Burdensome Issues\"
document. It is available on our Center webpage at:
[http://www.fda.gov/cdrh/modact/leastburdensome.html](../../../../../../../../cdrh/modact/leastburdensome.html).

# DEVICE DESCRIPTION

You should provide a description of the device and its functional
components, including:

-   pictorial representations

-   engineering drawings

-   block diagrams of circuits.

The block diagrams of the circuits should trace signal flow, processing,
and logic of operation at the transducer level and the circuit level, as
appropriate. You should describe each of the functional components and,
for each, provide:

-   complete set of electrical schematics

-   complete set of mechanical drawings

-   detailed drawings and descriptions of all components including
    material composition

-   electrical specifications and, where appropriate, references to
    laboratory testing that established these specifications

-   mechanical specifications and, where appropriate, references to
    laboratory testing that established these specifications

> **Transducer**
>
> You should describe the type of transducer utilized to provide
> stimulation to the middle ear. Describe the size and frequency
> response characteristics of the transducer, and its effect on middle
> ear physiology (e.g., residual hearing). Describe the attachment and
> any mounting mechanism(s) necessary for adequate surgical placement of
> the transducer.
>
> **Attachment**
>
> You should describe the means of attachment of any external connector,
> transmitter or charging apparatus and the effects of hair and varying
> skin thickness, as appropriate. Include the effects on "normal" use
> activities (i.e., work environment, walking, running, swimming, etc.)
>
> **Radiopacity**
>
> You should describe the radiopacity of the device components or other
> means of localizing the implanted components.
>
> **Finite Element Modeling**
>
> You should describe parameter values used to model the normal middle
> ear system and the changes to the same as a consequence of implanting
> the device. Describe any Finite Element Modeling (FEM) of the middle
> ear, if possible.
>
> **Device Accessories**
>
> You should describe all device accessories, such as user controls,
> programming interface(s), software, cables, connectors, and
> audiological equipment provided and designed exclusively for your
> device. You should describe the type of battery used in the device and
> indicate the projected battery life. You should describe the battery,
> including whether or not it is rechargeable, and how it would be
> replaced, especially for a totally implantable IMEHD.

# MANUFACTURING

For guidance additional to that noted here, please refer to the
**Premarket Approval Manual**,
[http://www.fda.gov/cdrh/dsma/pmaman/front.html]{.underline}.

## Software Validation 

> Please refer to **Guidance for the Content of Premarket Submissions
> for Software Contained in Medical Devices,**
> [http://www.fda.gov/cdrh/ode/software.pdf](../software.pdf), for a
> discussion of the software documentation that you should provide. As
> discussed in the *Software Guidance*, the \"level of concern\" is
> related to the possible consequences of software failure, and may be
> minor, moderate, or major. The software for IMEHD is generally
> considered a \"moderate level of concern.\" If you believe that the
> software in your IMEHD should be considered a minor level of concern,
> you should provide a clear scientific justification, which discusses
> the possible consequences of a software failure.

We encourage you to take advantage of any FDA-recognized software
standards and provide statements or declarations of conformity. A
standard that may be used is ISO/IEC 12207: Information technology
software life cycle processes (Software), [Information Technology -
Software Life Cycle
Processes](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/Detail.CFM?STANDARD__IDENTIFICATION_NO=233).

> If the device includes off-the-shelf software, you should provide the
> additional information as recommended in the **Guidance for Industry,
> FDA Reviewers and Compliance on Off-the-Shelf Software Use in Medical
> Devices**,
> [http://www.fda.gov/cdrh/ode/guidance/585.html](../../../../../../../../cdrh/ode/guidance/585.html)

## Sterilization 

> You should submit the following information for IMEHDs sold as
> sterile:

-   the sterilization method used in the sterilization cycle (e.g., dry
    heat, ethylene oxide (EtO), steam, radiation);

-   a description of the method that will be used to validate the
    sterilization cycle;

-   a description of the packaging that maintains the device\'s;

-   the sterility assurance level specification (SAL); FDA recommends
    10^-6^ for implanted components labeled sterile;

-   a description of the method used to make the determination, e.g.,
    the limulus amebocyte lysate (LAL) method, if the product is labeled
    pyrogen free;

-   the maximum levels of EtO and ethylene chlorohydrin residues, if
    sterilized by EtO; and

-   the radiation dose, if sterilized by radiation.

> All IMEHDs labeled sterile should have expiration dating.
> Determination of expiration dating involves assessing the barrier
> properties of the packaging to assure sterility. In addition, certain
> devices should be tested to assure that storage and shipping
> conditions do not alter their function and that they function the same
> as when manufactured.
>
> In addition to the following sterilization standards, there may be
> other standards that are useful. If you use a FDA-recognized standard,
> you may submit a declaration of conformity in lieu of performance
> data. See **Recognition and Use of Consensus Standards; Final Guidance
> for Industry and FDA Staff**
> <http://www.fda.gov/cdrh/ost/guidance/321html>. See also CDER
> guidance: Guideline on validation of the Limulus Amebocyte Lysate Test
> as an end-product endotoxin test for human and animal parenteral
> drugs, biological products and medical devices.
> <http://www.fda.gov/cder/guidance/old005fn.pdf>

-   ANSI/AAMI/ISO 11134 - Sterilization of health care
    products-Requirements for validation and routine control of
    industrial moist heat sterilization

-   ANSI/AAMI/ISO 11135 - Sterilization of medical devices -Validation
    and routine control of ethylene oxide sterilization

-   ANSI/AAMI/ISO 10993- 7 - Biological evaluation of medical devices -
    part 7: Ethylene oxide residuals

-   ANSI/AAMI/ISO 11137 Sterilization of medical devices -Validation and
    routine control - radiation sterilization

-   ANSI/AAMI/ISO 11607 Packaging for terminally sterilized devices

```{=html}
<!-- -->
```
-   USP 24:2000 (85) Biological Tests and Assays, Bacterial Endotoxin
    Test (LAL) or

> USP 24:2000 (151) Pyrogen Test (USP Rabbit Test)
>
> []{#__RefHeading___Toc9070390 .anchor}4. PRECLINICAL INFORMATION

## Design Characteristics of IMEHD

> **Design safety mechanisms**
>
> You should describe specific design provisions that limit or prevent
> excessive stimulation of the subject\'s middle and inner ear
> structures.
>
> **Surgical placement**
>
> You should describe the design provisions that accommodate anatomical
> variations. You should also describe the implant site and the design
> characteristics that have been incorporated to facilitate surgical
> placement.
>
> **Implant stability**
>
> You should describe the design provisions that promote long-term
> implant stability and prevent device movement (e.g., during pressure
> changes, tympanometry, impact, or injury). You should include pull
> testing parameters, data, and analyses to demonstrate that the force
> of detachment of the device from an ossicle is lower than the force
> required for disarticulation.
>
> **Biomechanical function**
>
> You should describe the design provisions that facilitate the normal
> biomechanical function of the middle ear(s) after implantation.

## System Output and Response

> The design of an IMEHD may limit your access to system component
> output measures for your use during final testing. Pre- and
> post-implant test methods should provide objective test data within
> practical limits of the design of the device.
>
> **Pre-implant testing**
>
> You should evaluate each component of the external and internal
> implant system prior to final assembly. Your evaluation should ensure
> that each system component and implant subsystem operates within your
> defined specifications. You should provide the results as a graph,
> table or text, as appropriate. You should provide a discussion of the
> results including conclusions.
>
> For semi-implantable IMEHDs, you should describe methods of testing
> external and internal unit performance against your input/output
> specifications.
>
> For totally implantable IMEHDs, you should describe methods of testing
> unit performance against your input/output specifications.

## Biocompatibility

> You should evaluate the biocompatibility of the materials used in your
> device. Please refer to the guidance document entitled **Blue Book
> Memo, G95-1***,* **Use of International Standard ISO-10993,
> \"Biological Evaluation of Medical Devices Part 1: Evaluation and
> Testing\"** <http://www.fda.gov/cdrh/g951.html>.
>
> You should select biocompatibility tests appropriate for implant
> device; tissue/bone contacting; intended for permanent duration. See
> ANSI/AAMI/ISO 10993-1 - Biological Evaluation for Medical Devices Part
> 1, Evaluation and Testing. If you use an FDA-recognized standard, you
> may submit a declaration of conformity in lieu of performance data.
> See **Recognition and Use of Consensus Standards; Final Guidance for
> Industry and FDA Staff**
> [[http://www.fda.gov/cdrh/ost/guidance/321html]{.underline}](http://www.fda.gov/cdrh/ost/guidance/321html).

## Animal Studies

> Depending on the design of your device, animal studies may be
> necessary to support the safety and performance of your device. If you
> conduct animal studies, the reports should include:

-   protocol

-   objective of the study

-   experimental design (including type and number of animals used)

-   method of performing the study

-   auditory evoked response testing

-   histology with particular attention to regions of device attachment

-   type and number of animals used.

> You should provide an analysis of the data and a description of any
> modifications made to the device as a result of this testing. If
> conducted, animal studies should be of sufficient length to allow for
> evaluation of tissue remodeling.

## Environmental Testing

> You should demonstrate the reliability and performance of external
> components, as appropriate, under various operating and storage
> conditions (e.g., temperature, vibration, handling, and electrostatic
> discharge). You should provide test information demonstrating the
> longevity of external components, including battery-powered
> components.
>
> You should provide results of environmental tests (e.g., dry heat,
> cold temperature, hermeticity, free fall, thermal cycling, vibration
> impact shock, weld tests, lead stretch and flex test, failure mode
> analysis).
>
> Standards that address environmental testing for your device include:

-   IEC 68 Basic environmental testing procedures

-   EN 45502-1: Active implantable medical devices-Part 1: General
    requirements for safety, marking and information to be provided by
    the manufacturer

-   ISO 6474: Implants for Surgery -- Ceramic materials based on high
    purity alumina

> **Electromagnetic Compatibility (EMC) Testing**
>
> You should demonstrate the effect of mobile telephones, cellular
> telephones, walkie talkies, or other potential sources of
> electromagnetic interference on the entire device, including external
> and internal (implanted) components. EMC testing should demonstrate
> reasonable assurance that use of the device with such electrical
> products results in neither serious bodily injury nor device
> malfunction or failure.
>
> You should use the test methods in ANSI/IEEE C63.19-2001 American
> National Standard for Methods of Measurement of Compatibility between
> Wireless Communications Devices and Hearing Aids. Testing should
> include magnetic field immunity to electromagnetic fields emitted from
> anti-theft systems and security systems (Electronic Article
> Surveillance Systems, Walk-Through Metal Detectors, and Hand-Held
> Metal Detectors). Other EMC testing should be done in accordance with
> accepted electromagnetic immunity standards such as IEC 60601-1-2
> Medical Electrical Equipment - Part 1: General Requirements for
> Safety; Electromagnetic Compatibility -- Requirements and Tests
> (General).
>
> **Magnetic Resonance Imaging (MRI) Compatibility Testing**
>
> If you intend that your device be safe for MRI, you should evaluate
> its compatibility with MRI. You should perform all MRI compatibility
> testing on finished devices. You should also assess the magnetically
> induced forces and torques on the device during imaging. You should
> also address any potential risk to the patient due to induced
> electrical currents and functional disruption of the operation of your
> device caused by its presence in a magnetic field.
>
> You should determine the magnetically-induced deflection force for a
> paramagnetic material at the location where the product of the
> magnitudes of the magnetic field and the spatial gradient of the
> magnetic field, $|B|$ $|\nabla B|$, is at a maximum. You should also
> determine the magnetically-induced deflection force for a saturated
> ferromagnetic object at the location where the spatial gradient in the
> magnetic field is a maximum. It is possible that these locations are
> off the central axis of the bore of the scanner. The
> magnetically-induced torque is a function of the field strength;
> therefore, you should measure it where the static magnetic field is
> the greatest within the bore of the magnet. We expect that the
> physical location of the maximum torque and displacement force be
> different.
>
> You should assess the heating of the device produced by the magnetic
> and radio frequency (RF) fields during imaging. You should also assess
> gradient induced voltages and image artifacts. Final testing should
> use sequences that will produce maximal distortion in the image and
> maximal heating to evaluate the worst case conditions for both. Please
> provide copies of the images showing the distorted regions.
>
> Because MRI technology is changing rapidly and systems with larger
> magnetic fields are being introduced on the market, any claims for
> compatibility of the device with the MR environment should include a
> description of the field conditions under which it was tested.
>
> Standards that address MRI safety and compatibility are:

-   ASTM F2052-00: Standard Test Method for Measurement of Magnetically
    Induced Displacement Force on Passive Implants in the Magnetic
    Resonance Environment

-   ASTM F2119-01: Standard Test Method for Evaluation of MR Image
    Artifacts From Passive Implants

-   IEC 60601-2-33 - Medical Electrical Equipment - Part 2: Particular
    requirements for the safety of magnetic resonance equipment for
    medical diagnosis

## Electrical Testing

> The device should meet the electrical safety requirements of IEC
> 60601-1, Medical Electrical Equipment Part 1: General Requirement for
> Safety, (General); Amendment 1, Amendment 2. EN 1441: Medical Devices
> Risk Analysis (General) may also apply.

## Stress, Fatigue, and Wear

> You should evaluate the stress, fatigue, and wear properties of your
> device (as a system) and its materials. You should also evaluate the
> flexure performance of any implanted leads that connect system
> components. You should select engineering tests appropriate for the
> design of your device and describe the rationale for your selection.
> If you use an FDA-recognized standard, you may submit a declaration of
> conformity in lieu of performance data. However, if you have modified
> a test method, used a test method from a standard that is not
> recognized, or developed your own test method, you should provide a
> complete description of the test method and the data.

## Reliability

> You should evaluate the physical properties of the implanted device
> after prolonged exposure to the biological environment. *In vitro*
> physiological model testing may serve in place of an animal study,
> provided that you have already demonstrated the biocompatibility of
> the materials in the implanted device. Alternately, you may conduct an
> animal study that includes a sufficient number of devices (one per
> animal) implanted into the middle ear of suitable animal models for
> sufficient lengths of time to provide reasonable assurance of safety
> and effectiveness as a long term implant.
>
> You should assess the system reliability both predictively and
> retrospectively. Note: predictive techniques include tolerance
> analysis, fault tree analysis (FTA), failure mode effect criticality
> analysis (FMECA) and mean time between failure (MTBF) prediction.
> Retrospective techniques include demonstrations of reliability through
> environmental and accelerated stress tests as well as FTA and FMECA of
> *in vivo* and *in vitro* failures. You should discuss design revisions
> that result from the system reliability analyses. Particular attention
> should be given to failures that could injure the patient, create
> excessive noise or discomfort, or require revision surgery. Software
> system(s) and safety should be discussed in detail.
>
> You should discuss the techniques for predicting and testing the in
> vivo reliability and stability of implanted components. You should
> provide the rationale and test data supporting your selection of:

-   electronic components

-   attachment materials

-   lead materials

-   joining methods and sealing techniques.

> The reliability analysis should address predictive analyses as
> described above. You should provide special emphasis on:

-   methods and data used in FMECA

-   tolerance analysis

-   determination of FMECA categories.

> You should provide retrospective methods with special emphasis on:

-   methods and data used to evaluate *in vitro* and *in vivo*
    reliability of implanted components

-   environmental test methods and results for nonimplanted components.

> A standard that addresses may address reliability of the device as a
> result of shipment is ASTM D4169: Standard Practice for Performance
> Testing of Shipping Containers and Systems.

# INVESTIGATIONAL DEVICE EXEMPTIONS

Studies involving these devices should comply with the regulations
governing institutional review boards (21 CFR 56) and informed consent
(21 CFR 50). See also Appendix B Informed Consent. In addition, because
FDA has determined this device is a significant risk device as defined
in 21 CFR 812.3(m), these studies should have an FDA-approved IDE (21
CFR 812).

## Clinical Protocol

> You should conduct a within-subject repeated measures clinical study
> to demonstrate safety and effectiveness of the IMEHD. The sample size
> should be sufficient to provide a power of .80 (α = .05). Appropriate
> sample size allows you to attribute the outcome to the intervention
> rather than chance effects alone. Refer to the Clinical Results
> Section below for additional information. FDA recommends that the
> study have at least three investigators at different locations, each
> with a sufficient number of subjects to support the study design.
>
> **Investigators**
>
> The Principal Investigator at each study site should be a licensed
> physician who has training and experience in middle ear surgery and
> has received training regarding the surgical implantation of your
> device. Co-investigators should include audiologists who have
> knowledge and experience with current state-of-the-art air conduction
> (acoustic) hearing aid technology.
>
> **Subject selection criteria**
>
> You should specify the hearing loss degree, range and type indicated
> for the IMEHD. You should describe hearing impairment in each ear as
> determined by objective hearing tests. This should include pure-tone
> procedures including the test frequencies: 250, 500, 1000, 2000, 3000,
> 4000, 6000 and 8000 Hz.
>
> You should include a description of aided performance assessment:
> soundfield audiological evaluation (see preimplant protocol), i.e.,
> functional gain testing, real ear probe microphone testing, tolerance
> levels, and speech perception measures, as appropriate. Specify aided
> performance for each test measure of subjects selected for the study.
>
> You should measure and describe the subject's self-assessment with
> conventional acoustic amplification using a validated scale
> appropriate for the intended patient population.
>
> Describe any subject's inability to use conventional hearing aid(s)
> due to medical contraindication (e.g., external otitis).
>
> You should not include subjects who are contraindicated for undergoing
> implantation surgery (e.g., active infectious process, lesion of the
> acoustic nerve or central auditory pathway).
>
> You should specify whether or not you have included any subjects with
> an IMEHD in the non-surgical ear or any subjects undergoing revision
> (explanting previously implanted IMEHD with implantation of your
> device).
>
> If any deviations occurred, you should include a description of, and
> rationale for, the deviations from the subject inclusion criteria.
>
> **Study population**
>
> You should include the distribution of relevant variables:

-   Hearing aid use-e.g., current hearing aid user, previous user

-   Number of subjects in experimental and, when used, control groups

-   Age distribution

-   Etiology of hearing impairment, if known

-   Other pertinent variables, e.g., audiological history, age at onset
    of hearing impairment (including manner of determining age of onset)

> **Device Safety**
>
> You should discuss and analyze the following information when
> determining device safety.

-   You should evaluate and describe all residual-hearing changes in
    detail, including air and bone conduction threshold measures and
    speech perception testing results.

-   You should describe each adverse reaction and complication.

-   You should define device failure and provide a complete failure
    analysis report for each device failure.

> **Effectiveness measures and control conditions**
>
> You should describe in detail the pre-surgical aided condition for
> each subject. Pre-operative measures obtained without the use of
> hearing aids, or with hearing aids whose fitting and operational
> status is not optimized for the patient, may provide inadequate
> assessment of the control condition. You should define and justify
> your criteria for establishing that the fitting and operational status
> are optimal.
>
> Direct device comparisons (i.e., conventional hearing aid vs. IMEHD)
> are necessary to establish the benefit side of the risk benefit
> comparison. You should conduct baseline tests that document the
> benefit associated with alternative state-of the-art conventional
> hearing aids. You should incorporate the same or similar methods of
> fitting and signal processing with the conventional hearing aids as
> the IMEHD, if possible.
>
> **Preimplant and Postimplant Assessments**
>
> For both preimplant and postimplant assessments, you should conduct
> the following:
>
> **Presurgical medical examination** -- you should include a
> preoperative history, including whether tinnitus is present and an
> otologic evaluation with temporal bone radiology, if indicated. You
> should state the clinical criteria used to diagnose tinnitus.
>
> **Audiological assessment** -- you should measure and determine
> pure-tone air and bone conduction thresholds for each ear, tolerance
> levels, acoustic immittance measurements, speech reception thresholds
> and speech perception testing, including monosyllabic word material,
> sentence material and/or spondee (two syllable word) material. You
> should include the following frequencies for pure-tone air conduction
> testing: 250, 500, 1000, 2000, 3000, 4000, 6000 and 8000 Hz.
>
> **Soundfield assessment** -- You should include masking for the
> non-test ear during soundfield assessments.
>
> **Soundfield audiological assessment** -- you should include both
> aided and unaided conditions, e.g., warble-tone thresholds at 250,
> 500, 750, 1000, 1500, 2000, 3000, 4000, and 6000 Hz, including
> tolerance levels.
>
> **Soundfield speech perception testing** -- you should include
> verification of the intensity of the stimuli at the subject's ear.
> This is especially important when data are collected from several
> investigational sites having varying size sound suites containing
> varying numbers of objects. Speech perception testing should include
> more than one norm-referenced, standardized test, and should be
> conducted in quiet and in noise. Various intensity levels, such as
> average conversational speech level and PB-Max (Phonetically Balanced
> Maximum) level should be included. Estimates of test-retest
> reliability and alternate form equivalency should be addressed.
>
> **Monaural vs. binaural assessment** -- you should describe how you
> will address binaural benefit or lack thereof; and describe any
> variables or potential bias from the aided non-implant ear.
>
> **Self-assessment of communicative performance** should be measured in
> several conditions, such as untreated and with current means of
> treatment (e.g., conventional hearing aid, implant + conventional
> hearing aid, implant only, etc). You should include self-report
> inventories of subject satisfaction, attributes of satisfaction, use,
> or benefit in daily life in order to assess those properties outside
> of the laboratory setting. You should use test instruments that have
> been validated and for which normative data are available. You should
> provide the rationale for the instruments you select.
>
> **Counseling** -- you should include a detailed explanation of
> realistic expectations of the implant and how you will incorporate
> them into the investigational plan.
>
> In addition to the above, **during the preimplant assessment**, you
> should conduct real ear measurements with reference to a normed
> target. You should include a prescriptive target formula that is
> appropriate for the hearing aid circuitry used with a given subject.
>
> **Post-implant testing**
>
> You should evaluate output of the device after implantation. You
> should provide actual system and subsystem data to show that the IMEHD
> system is functioning within your defined specifications. You should
> conduct this testing as a part of the post-implant assessment of each
> subject in the clinical trial.
>
> You should describe the overall system vibrational output as a
> function of sound input including gain, phase, and frequency
> responses. The data should show the response characteristics of the
> transducer or transduction mechanism (i.e., vibrational output as a
> function of electrical input). Similarly, you should describe the
> contribution of the transducer to the overall system response. You
> should describe the middle ear transfer function of each system
> component, including potential effects on overall system response due
> to attachment to a complex mechanical load (i.e., the middle ear
> system).
>
> When possible, you should measure vibration of the middle ear using a
> fresh human temporal bone, which approximates the in-vivo system. You
> may use, for example, laser vibrometry to completely describe the
> system responses of the human ear. You should provide a direct
> comparison relating the vibration data to equivalent mechanical
> vibrations induced by sound input to the ear \[i.e., decibel (dB)
> output from the device referenced to equivalent decibel sound pressure
> level (dB SPL)\].
>
> Describe the characterization of the level and duration of stimulation
> with evidence of the safety of this level.
>
> Standards that may partially apply to device function include:

-   ANSI S3.22: Specification of Hearing Aid Characteristics

-   ANSI S3.42: Testing Hearing Aids with a Broad-Band Noise Signal.

> **Surgical concerns**
>
> You should describe the incision type, the surgical approach (e.g.,
> facial recess, mastoidectomy) to be used, how the device is attached
> to the appropriate vibratory structure of the ear, how anchoring
> assemblies (if required) are utilized. You should detail the critical
> technical portions of the surgery (i.e., device placement). Include an
> estimate of the required surgical time required for device
> installation. You should specify the recommended type of anesthesia.

You should describe pre-surgical and post surgical care that will be
required for each subject.

You should describe any limits or considerations for the use of standard
surgical and otologic instruments (e.g., monopolar electrocautery after
placement of the implant).

> **Monitoring**

Clinical investigators should monitor patients closely with [100 percent
follow-up]{.underline} or with a detailed explanation for any loss of
follow-up.

You should specify the minimum length of follow-up postimplant. You
should describe how dropouts or lost to follow-up will be counted in the
analysis.

# CLINICAL RESULTS

You should present and thoroughly describe the results of the
statistical analyses of the clinical investigation in the PMA. You
should include the statistical methodology and rationale for each test.
Include references and formulas for each methodology. You should
describe and explain any deviations from the methodology.

The primary endpoint of a study design should be directly related to the
statements regarding device safety and effectiveness. You should state
the study hypothesis and describe how the endpoint either supports or
rejects the hypothesis. You should include a sufficient number of
patients and complete follow-up at regular intervals in order to
determine the safety and effectiveness of the device.

You should determine the sample size based on a power analysis, and at a
minimum, you should set the sample power set to 0.8 and alpha to 0.05.
You should analyze the data to describe the success or failure rate and
the complication rate.

You should provide a statistical analysis that is based on a subject
serving as his/her own control. The analysis should use appropriate
characteristics and measurement endpoints. You may use traditional
parametric, non-parametric or Bayesian analyses.

You should define the level of improvement that constitutes a clinically
significant change in the study. You should describe and justify the
method used to determine this level.

You should also provide the following information as part of this
section:

-   summary table specifying duration of follow-up for each subject in
    the investigation

-   statement as to why a study was discontinued, if it was, or a
    statement that it is continuing, if such is the case

-   tabulations of data from all individual subject report forms

-   patient complaints

-   methods used to eliminate bias on the part of the subjects or
    investigators.

-   copies of case report forms for each subject who did not complete
    the investigation

-   any interim analyses that were performed with adjustment of alpha,
    if indicated.

All tables and graphs should be accompanied with appropriate text so
that they are able to stand alone in the submission. You should provide
a detailed index of tables and graphs to facilitate review. The
following are examples of tables which may be helpful in presenting
results.

Demographics

  ----------- --------- --------- ---------- ------------ ------------ -----------------
  **Subject   **Age**   **Sex**   **Degree   **Hearing    **Binaural   **Years
  ID**                            of Hearing aid(s) Make  or Monaural  experience with
                                  Loss**     & Model**    fitting**    amplification**

                                                                       

                                                                       

                                                                       
  ----------- --------- --------- ---------- ------------ ------------ -----------------

Unaided Audiological Results, Air Conduction

+-----------------+-----+------+-----+------+------+-----+-----+----+
| **Subject ID:** | **  | *    | **  | *    | *    | **  | **  | *  |
|                 | 250 | *500 | 1.0 | *2.0 | *3.0 | 4.0 | 6.0 | *8 |
|                 | H   | Hz** | kH  | k    | k    | kH  | kH  | .0 |
|                 | z** |      | z** | Hz** | Hz** | z** | z** | k  |
|                 |     |      |     |      |      |     |     | Hz |
|                 |     |      |     |      |      |     |     | ** |
+-----------------+-----+------+-----+------+------+-----+-----+----+
| Pre-Op          |     |      |     |      |      |     |     |    |
|                 |     |      |     |      |      |     |     |    |
| Threshold       |     |      |     |      |      |     |     |    |
+-----------------+-----+------+-----+------+------+-----+-----+----+
| Post-Op         |     |      |     |      |      |     |     |    |
|                 |     |      |     |      |      |     |     |    |
| Threshold       |     |      |     |      |      |     |     |    |
+-----------------+-----+------+-----+------+------+-----+-----+----+
| Difference      |     |      |     |      |      |     |     |    |
+-----------------+-----+------+-----+------+------+-----+-----+----+

Unaided Audiological Results, Bone Conduction

  ----------------- --------- ------- -------- --------- --------- ---------
  **Subject ID:**   **250     **500   **1.0    **2.0     **3.0     **4.0
                    Hz**      Hz**    kHz**    kHz**     kHz**     kHz**

  Pre-Op Threshold                                                 

  Post-Op Threshold                                                

  Difference                                                       
  ----------------- --------- ------- -------- --------- --------- ---------

# MODIFICATIONS TO APPROVED DEVICES

A PMA Supplement is required for a change affecting the safety or
effectiveness of an approved device, unless FDA has advised you that an
alternate type of submission is appropriate for a particular change. You
should refer to the regulation on PMA Supplements 21 CFR 814.39. You
should also see PMA Supplements and Amendments on CDRH's Internet Device
Advice
[[http://www.fda.gov/cdrh/devadvice/supplements.html]{.underline}](http://www.fda.gov/cdrh/devadvice/supplements.html).

FDA believes that a PMA supplement may be necessary when you:

-   change the design of the audio processor or implant

-   change the circuitry, such as changing from analog to digital,

-   add new accessory devices

-   modify the indication for use.

We encourage you to contact the FDA review division staff for guidance
on whether your changes may require you to submit a supplement.

# APPENDIX A. INFORMED CONSENT

Subject informed consent must comply with 21 CFR Part 50. You should
describe any reasonably foreseeable risks or discomforts. 21 CFR
50.20(a)(2). For an IMEHD, these should include:

**Short term risks/discomforts**

-   loss of any residual hearing in the implanted ear as a result of the
    surgery

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-   injury to the facial nerve

-   meningitis

-   perilymph or cerebrospinal fluid leakage

-   electrical or mechanical failure of the device requiring its removal

-   revision/reinsertion

-   infection

-   blood or fluid collection at the site of surgery

-   vertigo

-   tinnitus

-   facial twitch

-   taste disturbances

-   a numbness or stiffness about the ear

-   a lump behind the ear

**Long term risks/discomforts**

-   necrosis

-   disarticulation of the ossicular chain

-   bone growth with potential damage to the auditory system

-   calcification

-   adhesions

-   other potential unknown long term effects on the auditory system.

You should also include these reasonably foreseeable risks for an IMEHD:

-   The possibility that it may be necessary to remove the device and/or
    utilize other methods in an attempt to regain hearing, such as
    reconstructive surgery and use of Total Ossicular Replacement
    Prostheses (TORPs) or Partial Ossicular Replacement Prostheses
    (PORPs). Include risks of revision procedure(s).

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-   A statement that MRI is contraindicated after implantation, if
    applicable.

-   The necessity for an external speech processor, if applicable (i.e.,
    with semi-implantable device).

-   Surgical removal of the battery, if applicable (i.e., with totally
    implantable device).

You must disclose appropriate alternative procedures or treatments. 21
CFR 50.20(a)(4). For an IMEHD, you should discuss other implantable
middle ear hearing devices and other recognized communicative systems
and devices, such as conventional acoustic hearing aids.

# APPENDIX B. LABELING

**General Information**

General labeling requirements for medical devices are described in 21
CFR 801. Additional labeling information may be obtained from the
guidance, **Medical** **Device Labeling Guidance #G91-1**
[[http://www.fda.gov/cdrh/g91-1.html]{.underline}](http://www.fda.gov/cdrh/g91-1.html).
You must submit all proposed labeling. 814.20(b)(10). These should
include package labels, a package insert, a Surgeon's Manual, an
Audiologist's Manual, a Patient Information Brochure, and a Patient
Identification Card. When developing the patient labeling, you should
refer to "**Guidance on Medical Device Patient Labeling**" which is
available at [http://www.fda.gov/cdrh/humfac/1128.html]{.underline} and
our information regarding plain language at
[http://www.plainlanguage.gov]{.underline}.

**Package Labels**

The outer package label(s) for IMEHD should include, at a minimum, the
following information:

-   device name, model, etc.

-   name and address of manufacturer

-   quantity

-   material

-   "Sterile," "Do not resterilize," and "Single use only" notations (or
    similar wording)

-   expiration date.

-   The label of the device packaging must bear the prescription device
    statement in accordance with 21 CFR 801.109(b)(1) "CAUTION: Federal
    law restricts this device to sale, distribution, and use only upon
    the lawful order of a physician."

**Package Insert**

The package insert for IMEHD should contain the following information:

-   package contents

-   device name, model, etc.

-   indications for use

-   "Sterile," "Do not resterilize," and "Single use only" notations (or
    similar wording)

-   expiration date

-   name and address of manufacturer

-   contact information for customer service inquiries

-   brief device description of all implanted and external components
    (if any)

-   indications for use

-   individualization of treatment section outlining specific patient
    selection criteria

> **Contraindications**
>
> For IMEHD, this section will generally usually include patients with:

-   conductive hearing loss

-   retrocochlear or central auditory disorder

-   active middle ear infections

-   tympanic membrane perforations associated with recurrent middle ear
    infections

> Additional or different contraindications may apply depending on the
> specific design or intended use of the device.
>
> **Warnings**
>
> At a minimum, you should include the following if applicable to your
> device:
>
> **MRI or strong magnetic fields**: Implanted patients should not be
> subjected to MRI and should not enter an MRI Suite or come into close
> proximity to other sources of strong magnetic fields.
>
> **Electrosurgery**: Electrosurgical instruments are capable of
> producing radio frequency voltages that can directly couple the
> instrument tip with the implant. Monopolar electrosurgical instruments
> should not be used within the vicinity of the implant because the
> induced currents could cause damage to the implant or the patient's
> hearing.
>
> **Diathermy**: Do not apply diathermy over the device because the high
> currents induced into the implant could cause damage to the implant or
> the patient's hearing.
>
> **Electroconvulsive therapy**: Do not use electroconvulsive therapy
> because it may damage the implant or the patient's hearing.
>
> **Other procedures**: A statement that the effects of cobalt
> treatment, PET scans, transcranial diagnostic ultrasound, and linear
> acceleration techniques on the implant are unknown.
>
> **Precautions**

Precautions alert the reader to exercise special care necessary for the
safe and effective use of the IMEHD. You should consider including the
following labeling precautions, if appropriate, for your device:

> **Damage**: You should list activities or conditions that could damage
> or affect the performance of the device including contact sports,
> extremes in temperature (e.g., blow dryers), moisture, hair care
> products.
>
> **Theft and** **Metal Detection Systems**: Theft and metal detection
> systems may activate the detector alarm of these systems. Therefore,
> patients should carry their Patient Identification Card with them at
> all times.
>
> **Ingestion**: You should include precautions against ingestion of any
> part of the IMEHD system. In particular, button cell batteries are
> harmful if swallowed. You should include instructions for immediate
> consultation with a physician and/or the National Button Battery
> Hotline (1-202-625-3333).
>
> **Fitting**: You should also include any specific precautions related
> to fitting of the device (e.g., earmold impression).
>
> **Clinical Considerations**
>
> This section should include a general description of evaluation
> procedures (e.g., audiometric tests, questionnaires, and conventional
> hearing aid evaluations) to determine candidacy for the IMEHD.
> Additionally, you should include the following sections:
>
> **Adverse and Potential Adverse Events -** You should include a table
> listing the type and number of adverse events. You should report the
> total number of patients implanted (i.e., the denominator) and the
> time period covered for the adverse events listed.
>
> **Clinical Study Summary -** This section briefly summarizes the
> safety and efficacy results of the clinical trials.
>
> **Clinical Study Results -** You should include a detailed
> presentation of the clinical study results including descriptive
> statistics, figures, and tables.
>
> **Information for Use and Recommended Training**
>
> You should describe the surgical expertise (e.g., experience in middle
> ear surgery, stapedectomy) and any other specific training required
> for the implantation procedure.

**Surgeon's Manual**

The Surgeon's Manual should include all information contained in the
Package Insert (indications for use, contraindications, warnings,
precautions, etc.) unless the two are in a combined manual.
Additionally, you should include the following items within the
Surgeon's Manual:

-   a clear description of all device components, accessories, and
    surgical tools used for implantation.

-   procedures for preoperative preparation of the patient (e.g.,
    prophylactic antibiotics), operating room (e.g., what supplies
    should be on hand), and troubleshooting procedures.

-   instructions for implantation, including placement of incision and
    thickness of skin flap, surgical approach (e.g., mastoidectomy,
    facial recess approach), proper seating and securing of the
    implantable device components into position, and any specific wound
    closure instructions.

-   warnings regarding potential surgical hazards associated with the
    implantation procedure and suggested measures to avoid/minimize
    them.

-   warnings, if applicable, regarding the use of monopolar cautery
    during the procedure to avoid damage to the implant or injury to the
    patient.

-   intraoperative test procedures to ensure implant integrity and
    proper placement (if necessary).

-   instructions for follow-up, including whether patient antibiotic
    prophylaxis is recommended during the post-implant period and during
    any subsequent surgical procedures, post-operative patient care,
    etc.

-   patient counseling instructions for device handling, maintenance,
    and storage (external components).

**Audiologist's Manual**

The Audiologist's Manual should include all information contained within
the Package Insert (indications for use, contraindications, warnings,
precautions, etc.) unless the two are in a combined manual.
Additionally, you should include the following items within the
Audiologist's Manual:

-   a clear description of all device components, accessories, and
    fitting instruments/kits

-   suggested timetable for initial post-operative visits for fitting
    and programming audio processor and subsequent visits for
    adjustments and monitoring

-   stepwise instructions on programming of the audio processor (e.g.,
    setting the frequency ranges, gain, and compression ratios for
    individual channels)

-   assessment of patient's aided performance and adjustments for
    optimization of programming

-   troubleshooting

-   patient counseling instructions regarding device handling,
    maintenance, and storage

-   information on device registration warranty, repairs, and technical
    assistance

**Patient Information Brochure**

The Patient Information Brochure should not exceed the eighth grade
reading comprehension level so that it is easily read and understood by
most patients. You should keep technical terms to a minimum and define
them if used.

The Patient Brochure should include, at minimum, the following
information:

-   device name, style, etc.

-   brief device description with material information

-   indications for use

-   detailed description of the operation of the external processor (if
    applicable) including operation of all controls and
    checking/exchanging batteries

-   troubleshooting

-   relevant contraindications, warnings, and precautions as described
    in the "Package Insert" section above (should be placed in the front
    of the brochure)

-   potential complications, including the possible methods of
    resolution

-   anticipated benefits and risks (to give patients realistic
    expectations of device performance)

-   surgical alternatives and the benefits and risks of each

-   postoperative care, including what to expect after surgery, symptoms
    to tell doctor about immediately, length of recovery, physical
    limitations, etc.

-   additional information related to the device such as registration
    and warranty, loss and damage provisions, information regarding
    repairs

-   study safety and effectiveness results.

**Patient Identification Card**

Patient Identification Cards are carried by patients and allow them to
share accurate information about their device with others when required.
You should construct the card of a material durable enough to last for
the anticipated life of the device. The card should include the
following information:

-   device name, model and serial number

-   brief device description

-   patient name, address, telephone number

-   name and contact information for the implanting surgeon and hospital

-   manufacturer name and contact information

-   information regarding theft and metal detection systems that may be
    activated by the IMEHD

-   medical precautions including warnings against MRI, electrosurgery,
    diathermy, and electroconvulsive therapy as outlined in the "Package
    Insert" section above.