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Moderator: Irene Aihie

07-29-21/11:00 am ET

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FDA Webinar-Implanted BCI Devices for Patients with Paralysis or Amputation - Nonclinical Testing and Clinical Considerations Final Guidance

Moderator: Irene Aihie

July 29, 2021

11:00 am ET

Coordinator: Welcome and thank you for standing by. Today's call is being recorded. If you

have any objections, you may disconnect at this time. All participants are in a

listen-only mode until the question-and-answer session of today's conference. 

At that time, you may press Star-1 on your phone to ask a question.

I would now like to turn the call over to your host. Irene Aihie. You may

begin.

Irene Aihie: Thank you. Hello and welcome to today's FDA Webinar. I'm Irene Aihie of 

CDRH's Office of Communication and Education.

On May 20, 2021, the FDA published the Final Guidance, titled Implanted

BCI Devices for Patients with Paralysis or Amputation, Non-Clinical Testing

and Clinical Considerations.
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This Webinar will describe non-clinical testing recommendations associated

with implanted BCI devices for patients with paralysis or amputations with

industry and stakeholders.

This Webinar will also recommend clinical trial design to provide a

reasonable assurance of safety and effectiveness necessary to support a

regulatory submission and translation of BCI devices from concept to

assisting device users.

Today, Dr. Heather Dean, Assistant Director in charge of the Acute Injuries

Advisory Team in the Office of Neurological and Physical Medicine Devices

here in CDRH will share information about the final Guidance. Following the

presentation, we will open the lines for your questions related to information

provided during the presentation.

Now, I give you Heather.

Dr. Heather Dean: Thank you. So, first of all, I want to give a shout out of recognition to a

member of my team who put together this presentation, Dr. Julia Slocomb. 

She was unable to be here today, but she really did the work in putting this

together.

So, to get started, on May 20th, 2021, the U.S. Food and Drug Administration

published the Final Guidance document, Implanted Brain Computer Interface 

– or BCI Devices – for Patients With Paralysis or Amputation, Non-Clinical 

Testing and Clinical Considerations Guidance.

The focus of today's Webinar is to share information and answer questions

about the Final Guidance documents. During this presentation, I will provide

an overview of the purpose and key components of the Guidance Documents
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and highlight the differences between the Final Guidance document and the

Draft Guidance document.

Before we begin, I would like to review a few important terms that will be

used frequently during this presentation. Investigational device exemption – or

IDE – is a mechanism which allows an investigational device to be used in a

clinical study in order to collect safety and effectiveness data.

Q Submissions are a mechanism which you, as a researcher, can use to obtain

FDA feedback on future IDE applications prior to their submission. It is

typically used to review plan protocols, but not study data, which is addressed

only in a formal submission.

For the purposes of this Guidance document, implanted brain computer

interface, or BCI devices, are neuroprostheses that interface with the central or

peripheral nervous system to restore lost motor and/or sensory capabilities in

patients with paralysis or amputation.

Assistive effector components are a prosthetic limb, wheelchair, functional

electrical stimulators applied to an intact limb, exoskeletons, or robotic

systems or communication devices and computers.

The field of implanted BCI devices is progressing rapidly from fundamental

neuroscience discoveries to translational applications and market access. This

Guidance is a Leapfrog Guidance, a type of Guidance that serves as a

mechanism by which the Agency can share initial thoughts regarding

emerging technologies that are likely to be of public health importance early

in product development.
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This Leapfrog Guidance represents the Agency's initial thinking, and our

recommendations may change as more information becomes available.

The purpose of this Final Guidance document is to provide recommendations

to industry about the types of information to be included in your Q 

Submissions, and IDEs for implanted BCI devices for patients with paralysis

or amputation.

It is important to note that non-implanted BCI devices are not within the scope

of this Guidance, as the regulatory considerations of these devices may differ

from those recommended in this Guidance document, depending on various

aspects, such as, but not limited to the technical characteristics and indications

for use or patient population. For feedback on regulatory considerations for

non-implanted BCI devices, we recommend following the Q Submission

process.

BCIs are used both in health care and home settings, but implantation and

device training are always performed in health care settings. In health care

settings, they are used by health care professionals.

We're seeing more and more submissions which involve home use by lay 

users, i.e., patients with paralysis or amputation, with or without assistance

from caregivers. It is important to note that home use involves different

considerations when preparing an IDE Submission. This Leapfrog Guidance

impacts all stakeholders preparing Q Submissions and the IDEs for implanted

BCI devices.

The Draft Guidance was issued on February 22, 2019. We received many

comments through the docket during the 60-day comment period and further

comments from outside stakeholders, not through the docket.
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We used these comments as a basis for several significant changes to the

Guidance, which are reflected in the Final Guidance. The Final Guidance was

issued on May 20, 2021. Most of the recommended testing remains

unchanged compared to the Draft Guidance.

However, in addition to minor changes in wording and grammar to improve

clarity, important clarifications and additions were made to the sections listed

here. 

The Guidance includes recommendations for the sections shown here, which I

will review in the remainder of my presentation.

We recommend that you include in your submission a device description, 

including 1) A complete description of every module of the device.

For example, BCI Systems typically consists of several modules including,

but not limited to, the following modules: signal acquisition, for example, 

leads and recording electrodes; signal processing that includes software for

decoding and encoding signals and providing stimulation, in some cases, and

associated hardware; stimulation delivery, including internal and external

stimulators and stimulating electrodes; assistive effector components, as

defined earlier; sensor components for neural feedback, for example, sensors

for restoring touch or recording other information, if applicable; and a

programming module that consists of an operating protocol to control

functions, such as turning the device on and off and switching between

various outputs and programs.

The description should also include, 2) A general overview of the BCI device

as a whole system, including a description of how the different modules are
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configured to comprise the whole system and, if applicable, a description of

the different system configurations (for example, programming, calibration or 

testing configurations).

3) A complete description of key components of the device, including its 

function, relevant model numbers, material, location, implanted or external 

components, and dimensions or sizes that a user would need to know how to 

use the device properly.

The Final Guidance recommends that if any key components were previously 

cleared or approved, the pre-market submission number, i.e., 510(k) or PMA 

number, with a description of modifications to the cleared or approved device 

should be provided.

While I won't be reviewing the rest of the recommendations for the device 

description in detail here, I would like to note that the Guidance provides an 

outline of recommended information for a variety of specific components.

Our biggest concern is patient safety. So, we recommend that you apply risk 

management principles as detailed in the Guidance during the development of 

your device. We recommend that the risk analysis detail qualitative 

examination of the potential hazards (for example, hardware, software, nonclinical related and clinical related hazards) of the device from the perspective 

of the user.

We also recommend identification of hazards caused by single-fault 

conditions to ensure that the failure of any single component of the implanted 

BCI device does not cause an unacceptable risk during use.
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The risk analysis should be provided in a tabular format and should analyze 

all potential causes for the identified risks.

Software in implanted BCI devices ensures that various components of the 

implanted BCI system, such as the signal processing modules, controllers, 

simulation hardware and assistive device, operate as intended and provide 

software mitigations when appropriate. Adequate software performance 

testing provides assurance that the device is operating within safe parameters.

Overall, software documentation should provide sufficient evidence to 

describe the role of the software included in the device, risks associated with 

the device, and performance testing to demonstrate that the software functions 

as designed.

We generally consider the software for implanted BCI devices to present a 

major level of concern. If you believe that the software in your device presents 

either a minor or a moderate level of concern as defined in the software 

Guidance, you should provide a scientific justification that supports your 

rationale for the level of concern based on the possible consequences of 

software failure.

For early feasibility studies, we recommend that you provide adequate 

software performance testing to provide assurance that the system operates 

within safe parameters. As appropriate, you should also provide information 

on the cybersecurity aspects of your device.

Human factors are also commonly referred to as usability and describe testing 

to understand how the device is typically used in real life. Use-related hazards 

are hazards resulting from failure modes tied to the use of implanted BCI 
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devices by end users (for example, patients, surgeons, prosthetists, 

caregivers).

They are a unique form of hazard in that use-related hazards can exist even if 

the device operates according to specifications. They generally do not involve 

specific failure modes associated with mechanical, electrical and software 

components that are previously known or reasonably anticipated.

These hazards might result from aspects of the user interface design that cause 

the user to fail to adequately or correctly perceive, read, interpret, understand, 

or act on information from the device.

Regardless of the severity of potential harm from a use-related hazard, it is 

important to understand and identify these hazards to ensure that you have 

designed a safe and usable device.

Human factors validation and evaluation is typically not needed to support 

feasibility study approval. However, it can be useful in demonstrating that 

home use is safe for users in an IDE application. Also consider that human 

factors data may be needed to support your future marketing submission to the 

Agency.

In order to address and mitigate use-related hazards in final device design, we 

recommend conducting usability evaluation (for example, cognitive walkthroughs, simulated use testing, satisfaction surveys) early in the device 

design process and iteratively throughout the device development and 

evaluation process.

If your device is still under development and you intend to pursue an early 

feasibility study for an IDE, the early feasibility study could be conducted to
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obtain initial insights into human factors (for example, difficulties in 

comprehending procedural steps and sufficient training, et cetera).

Implanted BCI devices contain patient-contacting materials, which, when used 

for their intended purpose (i.e., contact type and duration) may induce a 

harmful biological response. You should determine the biocompatibility of all 

patient-contacting materials present in your device. If the components of your 

BCI device are identical in composition and processing methods to 

components with a history of successful use in the same or similar anatomical 

locations, you may reference previous testing experience or literature.

The type of tests that are applicable to your device may depend on whether the 

electrodes interface with the central or peripheral nervous system. 

Additionally, devices intended to be used in conjunction with the implanted 

BCI device (for example, components or surgical tools) may contact the 

patient in different ways and for different durations.

The Guidance provides the biocompatibility endpoints associated with four of 

the most common categories for implanted BCIs, which I will not detail today 

in the interests of time.

It is important to note that while there are many ways to mitigate risks without 

performing complete testing for skin contacting devices, the risks for 

implanted devices are greater and there are fewer ways to mitigate risk for 

these devices without performing complete testing.

Implants and BCI devices should be adequately sterilized to minimize 

infections and related complications. For implanted BCI components and 

surgical tools labeled as sterile, we recommend that you include the 

information listed in the Guidance, some of which is summarized here.
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First, for the sterilization method, you should provide the following: A 

description of the sterilization method, chamber and site; in the case of 

radiation sterilization, the radiation dose; and for chemical sterilants, the 

maximum levels of sterilant residuals that remain on the device, and an 

explanation of why those levels are acceptable for the device type and the 

expected duration of patient contact.

Second, for the sterilization method, you should provide a description of the 

method used to validate the sterilization cycle (for example the half-cycle 

method) as well as the sterilization and validation data.

The submission should also identify all relevant consensus standards used and 

identify any aspects of the standards that were not met. In the absence of a 

recognized standard, a comprehensive description of the process and the 

complete validation protocol should be submitted and reviewed.

You should state the sterility assurance level (SAL) of 10-6 for devices labeled 

as sterile. We recommend that you describe the sterilization process validated 

for each sterile configuration.

Pyrogenicity testing is used to protect patients from the risk of febrile reaction 

due to gram-negative bacterial endotoxins and/or chemicals that can leach 

from a medical device, for example, material-mediated pyrogens.

To address the risks associated with the presence of bacterial endotoxins, 

implanted BCI devices should meet pyrogen limit specifications. Additionally, 

we recommend providing the routine batch release limulus amebocyte 

lysate (LAL) monitoring procedures.
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For devices intended to be labeled as non-pyrogenic, we recommend that both 

bacterial endotoxins and material-mediated pyrogens be addressed. 

Shelf life testing is conducted to support the proposed expiration date

through evaluation of the package integrity for maintaining device sterility 

and/or evaluation of any changes to device performance or functionality.

With respect to package integrity for maintaining device sterility, you should 

provide a description of the packaging, including how it will maintain the 

device's sterility, the protocols used for your package integrity testing, the 

results of the testing, and the conclusions drawn from your results.

We recommend that a package validation study include simulated distribution 

and associated package integrity testing as well as an aging process, which 

can be accelerated and/or real-time, and associated seal strength testing to 

validate package integrity and shelf-life claims.

We recommend you follow the methods described in the current edition of the 

FDA recognized consensus standards as listed here, or 11607–1, and 

ANSI/AAMI/ISO 11607–2.

With respect to evaluating the effects of aging on device performance or 

functionality, shelf life studies should evaluate the critical device properties to

ensure it will perform adequately and consistently during the entire proposed 

shelf life.

To evaluate device functionality, we recommend that you assess each of the 

non-clinical bench tests recommended in this Guidance, and repeat all tests 

that evaluate design components or characteristics that are potentially affected 

by aging, using aged devices.
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We recommend that you provide the protocols used for your shelf life testing, 

the results of the testing, and the conclusions drawn from your results.

We recommend all test samples undergo real-time aging to determine 

definitively the effects of aging on the maintenance, the sterility and the 

device performance.

Implanted BCI devices are medical electrical equipment and therefore 

may expose the operator and patient to hazards associated with the use of 

electrical energy or may fail to operate properly in the presence of 

electromagnetic disturbance.

Implanted BCI devices should be tested to demonstrate that they perform as 

anticipated in their intended use environments. We recommend that this 

testing be performed as described in the current FDA recognized versions of 

the standards for medical electrical equipment safety and electromagnetic 

compatibility shown here. If you have questions, please feel free to reach out 

to us via a Q-Submission.

In the design, testing and use of wireless medical devices, the correct, timely 

and secure transmission of medical data and information is essential for the 

safe and effective use of medical devices and systems.

BCI systems may utilize wireless connections to transfer neural signals, to 

control assistive technologies, or to drive electrical stimulation. If your 

implanted BCI device incorporates radio frequency wireless technology, such 

as Bluetooth, Wi-Fi, radio frequency identification (RFID) technology, or 

other wireless functionalities needed to perform the clinical function of your 

device, we recommend assessing the risk as described in the FDA recognized 
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version of AMII TIR 69: Technical Information Report Risk Management of 

Radio Frequency Wireless Co-existence for Medical Devices and Systems.

The selection of RF wireless operating frequency and modulation should take 

into account other RF wireless technologies and users that might be expected 

to be in the vicinity of the wireless medical device system.

These other wireless systems can pose risks that could result in medical device 

signal loss or delay that should be considered in the risk management process. 

If the risk management evaluation of the wireless function is found to be 

critical to the clinical function of the device, FDA recommends that you 

address your device's environmental specifications and needs as outlined in 

the current FDA recognized version of ANSI/IEEE C63.27.

MR imaging of a patient with an implanted BCI device poses a variety of 

potential hazards, including those shown here, which should be addressed in 

your IDE submission.

We recommend that you address the issues affecting safety and 

compatibility of your implanted BCI device in the MR environment as 

described in the FDA guidance, “Testing and Labeling Medical Devices for 

Safety in Magnetic Resonance (MR) Environment.”

In general, the typical duration of implantation should be considered when 

determining appropriate test methods for characterizing durability (for 

example, mechanical and electrical) of the components.

Testing should ensure that the device meets appropriate specifications that 

represent clinically relevant, worst-case in vivo conditions during device 

implantation and the expected life of the device.
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When appropriate, we recommend that the testing simulate the effect of any 

body fluids on the device components that come in contact with such fluids

(for example, after soaking in saline and before drying). We also recommend 

that you specify clinically justified acceptance criteria for testing.

We recommend that you include relevant information on the non-clinical 

bench testing provided in the form of test report summaries, test protocols, 

and complete test reports, as described in the guidance document, 

“Recommended Content and Format of Non-clinical Bench 

Performance Testing Information in Premarket Submissions.”

We recommend that the non-clinical bench testing outlined in the Guidance be 

addressed in your IDE, but today I will provide a brief overview of some of 

the key testing we recommend in the Guidance.

Electrodes can be used to measure physiological signals or provide the 

stimulation to the brain, spinal cord, and/or peripheral nerves or muscles for 

eliciting movement and/or sensation.

If the implanted BCI device includes electrodes, we recommend testing the 

following characteristics: dimensional verification and visual inspection, 

impedance, and accelerated lifetime testing.

Leads are used to connect electrodes to multiple components in an implanted 

BCI system, such as but not limited to, processing hardware and power 

modules. It is important that they function appropriately in the implanted BCI 

device system.
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We recommend testing to characterize the following attributes: dimensional 

verification and visual inspection, leakage current, lead body and connector 

flex fatigue testing, connector insertion and withdrawal forces, tensile strength 

of lead, particulate matter hazards, corrosion resistance, and compliance with 

21 CFR 898.12.

Electronics are often implanted, covered in a can or similar casing, which 

serve the process signals received from the leads and/or to provide electrical 

stimulation to the leads. We recommend you provide the testing listed here, 

which are detailed in the Guidance: hermeticity testing, environmental testing, 

header adhesion testing, and battery testing.

For devices that deliver electrical stimulation, it is important that the output

stimulation delivered by the device and stimulation output limitations are

appropriately characterized.

We recommend using methods described in ISO 14708–3: Implants for

surgery – active implanted medical devices - Part 3: Implantable neural

stimulators.

For each output mode, we recommend that you provide an oscilloscope trace 

describing the electrical output waveform under physiological loads that may

be encountered. The Guidance outlines specific information that should be

included with each trace. Traces should demonstrate ability to achieve

maximum stimulation settings in each trace and remain within specification.

Simulation output results can be recorded in the format recommended in

Appendix A of the Guidance. The Appendix includes a table which provides

an example of how information may be organized for a variety of example 

output modes.
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An output mode is defined, for reporting purposes, as a version of the

waveform produced by the unit. For example, biphasic symmetrical and

biphasic asymmetrical would be considered separate output modes. If multiple

values are available for a given parameter within the output mode, then the

manufacturer should provide the range and identify the different steps that

may be selected in that range if not continuous.

For devices that deliver electrical stimulation to the nervous system and

muscles, it is important that the output stimulation delivered to the tissue be 

safe for the intended use and stimulation duration. Excessive stimulation can

produce tissue damage that could result in serious injury or death depending

on the stimulation location.

We recommend that you provide scientific rationale (for example, literature

and/or animal studies outlined in the Guidance) to support the safety of the

stimulation output parameters (for example, maximum current, charge

density, current density charge per phase, frequency and duration).

An analysis of the safety of the output stimulation parameters provides

assurance that the risk of tissue damage is minimized during the use of the

device.

Hardware used to program stimulation parameters or select different device

modes are often called programmers or control units and may present risk to

the patients if they do not operate as intended.

We recommend that programmers / control units be subjected to verification

testing to assess electrical safety, functional, environmental, electromagnetic

compatibility, software, and reliability performance. For programmers or
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control units that can communicate with implanted electronics, testing

demonstrating that the programmer or control unit is capable of

communicating with and programming the implanted electronics should be 

provided.

If applicable, the transmitting and receiving antennae, transmitting distance, 

reed switch and magnet should be tested to ensure that they function as

intended. 

Radio frequency (RF) communication through a transmitter and receiver (such

as through inductive coupling) is sometimes used for programming or

controlling implanted components or recharging implanted batteries. 

RF transmitters and receivers may present risks to the patients if they do not

operate as intended. For example, inductive coupling may lead to tissue

heating or tissue damage.

Testing for the RF transmitter should include information outlined for the

programmer or control unit as described on the previous slide. In addition, we

recommend that you provide the testing for the RF transmitter, including

mechanical testing, electrical testing, and transmission distance and

orientation between the external emitting antenna and the antenna inside the 

receiver.

Testing for the transmitter and receiver should consider the testing

recommendations for wireless technology outlined in the wireless technology

section of the Guidance. To adequately demonstrate protection from heating

and ionizing radiation during the RF energy transfer, we recommend referring

to the currently recognized version of ISO 14708–3: Implants for surgery -

Active Implantable Medical Devices- Part 3: Implantable neurostimulators.
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Many BCI device technologies have multiple components that may be

interchangeable to achieve different and configurable clinical uses (i.e., a

modular approach). Given the variability of individual patient needs, 

manufacturers may choose to develop BCI systems with individual

components manufactured by different manufacturers, which allows a mix and

match compatibility across several device makers. 

Such individual components can be produced by different manufacturers and

subsequently combined to make a complete system. A thorough understanding

of how various components interact with one another, with the user and the

patient, and with the environment is essential to demonstrate the safety and

effectiveness of implanted BCI systems.

While each component of the system has characteristics that can introduce

risks individually, new risks can arise when the components interact to

perform as a system. To verify all system components operate together as set

forth by the system specifications, FDA intends to evaluate the entire system

and associated performance testing of the system. Electrical safety, 

electromagnetic compatibility, and wireless coexistence testing should be

performed on the full, complete system for the proposed intended use.

In addition, you should identify specific criteria that demonstrate

compatibility of the component with other device components and provide

scientific or clinical justification for the criteria.

However, if system-level testing is not feasible, a rationale for the exclusion

of system-level testing and description of how risk will be mitigated should be

provided. All devices intended to be used in conjunction with the implanted

BCI device (such as implantation tools, clips or belts for body-worn
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components, or components from another marketed medical device) should be

compatible.

Incompatibility can result in device damage or other clinical adverse events. 

Therefore, we recommend that you identify and provide specifications needed

to ensure compatibility between all modular components of the system in the

protocol and any labeling provided to the operators or investigator.

Often, researchers submitting an IDE need to use another party's product (for

example, material, sub-assembly or component) or use another party's facility

in the manufacture of the device.

In this circumstance where a researcher chooses to leverage information

related to the other party's product, facility, or manufacturing procedures in

their submission, a device Master File may be referenced as part of the

submission to FDA with a Letter of Authorization.

A Letter of Authorization is also required if referencing another researcher's

IDE in your submission. If you are using a cleared or approved device within

its approved indication, you do not need a Letter of Authorization to reference 

it in your submission.

But if you are using a cleared or approved device outside of its approved

indications, then we will require a Letter of Authorization from the

manufacturer.

Non-clinical animal testing is generally recommended to evaluate the in vivo

safety of implanted BCI devices, particularly for new designs, significant 

device modifications, and new indications.
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In most cases, we recommend that you conduct animal testing on a final

finished device to support the assessment that the risk to the subjects do not

outweigh the anticipated benefits to the subjects and the importance of the

knowledge to be gained in a human clinical trial.

We do understand that devices evaluated in early feasibility studies are often

undergoing modification, and in some scenarios, an animal study using a final

finished device may not be needed if an adequate rationale is provided.

Keep in mind that due to the variability in components, device designs, 

targets, and benefits in implanted BCIs, you may need to customize your

animal protocols to establish the data needed to support a future clinical study.

The Guidance outlines what to include in a typical animal study protocol, but I

wanted to outline a few general points regarding animal studies for implanted 

BCIs.

The main purpose for conducting an animal study is to provide evidence of

device safety. Animal studies may also provide evidence of device

performance that cannot be adequately obtained from bench testing, including

in vivo reliability over time.

However, alternative methods may be needed in situations in which animal

studies may be inappropriate, such as cognitive assessments. When designing

the study protocol, specific determinations of study variables such as the

number of animals studied, the study duration, the type of animal model or the

choice of controls depend on both the risks of the device and the existing

scientific information that can be used to mitigate expected risks.
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Existing scientific information with sufficient rationale may be leveraged to

lower the burden associated with conducting animal studies (for example, a

smaller number of animals or shorter duration of animal study) or justify why

additional animal studies may not be needed.

Many BCI devices involve implanted multi-component systems designed for

long-term use in human patients. For these devices, animal studies that

address chronic in vivo evaluation of the final device system provide a greater

degree of understanding of device safety than acute studies or chronic

investigations of partial systems.

A full evaluation of device risks and available scientific evidence will allow

for the determination of the appropriate protocol for a given BCI system. 

When describing the results of conducted animal studies, we recommend that

you include a discussion of how the findings support preliminary safety of the

device for your proposed clinical study.

Good laboratory practices – or GLP – for animal care and study conduct, as

specified in 21 CFR Part 58,ensure the quality and integrity of animal data to

support IDE applications.

Non-GLP study data may be used to support an IDE application only if the

deviations from GLP are identified and justified and do not compromise the

validity of the study results. I want to emphasize that we encourage you to

submit a Q-Submission prior to initiating your animal study to discuss your

animal model and study design.

The Guidance details some recommendations for an animal study design

evaluating BCI devices. Notably, the Guidance includes that the choice of
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animal models depends on the BCI device and may vary based on device type,

indication and implant site.

We believe that the animal and its related environmental and physiologic

attributes should provide a test system that offers the best attempt at

simulating the clinical setting.

Animal models that can accommodate human-sized devices may be

preferable, although the use of scaled devices might be acceptable in some

circumstances if appropriate scientific justification is provided. Appropriate 

controls should be identified in the study protocol. Generally, non-implanted, 

contralateral tissue is an appropriate control. 

We recommend histopathological or histomorphological evaluation of

implanted tissue, including both structural analysis and evaluation of injury

markers that are relevant to the neural tissue.

We recommend that you justify the use of specific histological markers and

provide evidence that the histological protocol is adequate to capture major

adverse reactions.

For devices involving a stimulation component, we also recommend that you

provide experiments to establish the safety of stimulation. Behavioral and

functional assays are recommended to better predict clinical adverse events.

For devices designed for chronic implantation, long-term device performance

should be established in a biological environment unless scientific evidence

for device performance in vivo has already been collected (for example, prior

animal studies and/or published literature using the same or similar electrode

configuration).
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In vivo impedance of electrodes and stimulation components may be required

to demonstrate and characterize the functionality of the device. The Guidance

details recommended testing, which should be performed for studies of either

acute or long-term stimulation. A detailed description of the implantation

approach should be provided along with its translatability to human

implantation.

For an IDE, a summary of any prior critical studies of the device used for the

proposed intended use must be provided in the report of prior investigations. 

For early feasibility studies, although clinical data may not be available with

the subject device for its proposed intended use, any relevant background

clinical information should also be provided.

This information may come from clinical use outside of the U.S. (OUS), but

you should justify its applicability to the patient population in the United

States.

Certain components of the clinical study design are especially important when

designing a clinical study intended to evaluate the performance of a BCI

system. For each clinical study design component, scientifically supported and

justified descriptions are essential to provide clarity and facilitate

understanding.

The following design components should be considered and supported with

the justification in your IDE submission when developing the clinical study

protocol.

First, a variety of patient populations may benefit from BCI devices whose

function is to augment their ability to interact with their environment and
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improve communication. Such populations include patients with limb

amputations or diseases and conditions, such as spinal cord injury, stroke, 

paralysis and neuromuscular disorders.

For an IDE approval, the potential benefit to the patient for any device should

outweigh the potential risks, and these may vary based on medical condition. 

Therefore, you should consider a subject population with needs that are

appropriately addressed by the device so that the potential benefits and risks

are appropriately considered.

We are seeing more studies incorporating home use into the research. It is

important to study BCI devices in realistic home-use environments, since lab

conditions may not adequately reflect the possible risks and/or benefits the

patients will experience during actual use in the environments in which the

patient will be using the device.

Additionally, for home use, it may be necessary to have a caretaker who is

willing, able and available to perform essential tasks related to the BCI

system. Therefore, it is important to incorporate assessment of caregiver

safety and their ability to assist the user (for example, time, attention, and

physical ability) in the clinical study metrics.

To ensure safe use of your device in the home setting, we recommend that

you specifically describe in your clinical protocol how subjects and caregivers

will be trained to use the device at home.

We also recommend that you describe how you plan to assess the

effectiveness of your training program. The BCI Guidance details how the

investigational plan can be developed for IDE studies for implanted BCI

devices.
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The following is an overview of some of the key aspects of our

recommendation.

First, the clinical protocol should begin with clearly-defined objectives and

hypotheses and an overall statement of the purpose or objective of conducting

the study, such as to evaluate the safety and effectiveness of the BCI device in

the treatment of specific conditions as compared to a control.

In addition, the purpose should include a precise, medically-accepted

definition of the condition to be treated and a scientifically sound rationale for

the proposed clinical study.

For pivotal clinical studies, the null and alternative hypotheses for the

proposed study should be stated in terms of the specific study endpoints, 

outcomes and parameters used to measure the success or failure of the system. 

The study should then be designed to test these hypotheses.

The Guidance details what your study design description should include, such

as the basic elements I have listed here. You should describe whether your

study is randomized; whether it is controlled, and if so, the type of control;

whether the study results will be compared to performance goal, and if so, 

how the performance goals were derived; a description of the study success

criteria; and a description of the patient success/failure if a responder analysis

is being used.

Additionally, studies may include more than one treatment group, such as

spinal cord injury, stroke or other conditions with proper justification as to

why the different populations can be pooled. We recognize that many studies

may not have well-defined performance goals or success criteria. And in those
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instances, we recommend that you submit a Q-Submission to discuss this with

us.

Next, study duration and follow up schedule.

In order to assess all safety and primary effectiveness outcomes sufficiently, 

the proposed study should include a sufficient amount of safety and an

appropriate level of effectiveness data. A long-term follow-up period of at

least one year is recommended due to the current lack of data regarding the

long-term effectiveness of implanted electrodes and to identify any long-term 

safety signals.

Long-term clinical durability and reliability are important factors to long-term

effectiveness of the implanted BCI device. For example, over time, implanted

electrodes can lose their ability to detect signals due to physical or biological

processes. Although some information on electrode durability and reliability

can be obtained from animal studies, animal studies may not accurately

predict long-term clinical performance in humans.

Apologies – give me just a minute to make sure that my computer is powered

because it seems to be losing power. There we go – apologies.

The clinical study protocol should include sufficient information regarding the

treatment parameters and protocol, including the implantation procedure, the

post surgical recovery period and regimen, the treatment duration and any

other surgical procedures anticipated, such as device removal.

The Guidance also provides recommendations relating to study endpoints and

other outcomes. The study safety endpoints should include a characterization

of all adverse events (or AEs) for all subjects, including, but not limited to,
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subjects in both the treatment and control groups, if applicable, and adverse

events related to the implant surgical procedure, the implantable device, and 

the assistive effective components.

The Guidance details information recommended with respect to safety

endpoints, primary and secondary effectiveness endpoints and validation.

We note that for this family of devices in particular, patient engagement

during clinical trial design may positively impact how an implanted BCI study

is designed and conducted. Patient preference information may be an

important factor, as previously mentioned, in the design and benefit-risk

evaluation of the medical device, including implanted BCI devices.

Additionally, risk tolerance may vary depending on the severity of the

disability. FDA recommends early discussion on a potential patient preference

information study to ensure its regulatory relevance. 

A patient-reported outcome measure can be used when the outcome of interest

and desired intended use are best measured from the patient's perspective, 

such as pain reduction.

In such cases, it is important to select a scoring assessment that is validated by

the appropriate context of use – in this case, subject, population and condition

being treated – and desired intended use. Early discussion with FDA during

the study design phase is important for studies of patient preference

information and for studies using patient-reported outcome measures.

The informed consent document must include all required elements and be

worded appropriately. We recommend ensuring that the document does not
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include language that could lead subjects to overestimate the chance of

personal benefit.

The statistical analysis plan will vary based upon the type of clinical trial. For 

example, a feasibility study may have a small number of subjects, and the

clinical study protocol may be designed to lead to an understanding of the new

therapy. Therefore, the statistical plan may be limited to descriptive statistics.

For a pivotal clinical study designed to demonstrate effectiveness, the study

protocol should include a detailed pre-specified statistical analysis plan that

includes plans to evaluate, to the extent possible, key assumptions that were

made in the design of the study.

The predefined statistical analysis plan should be adhered to in analyzing the

data at the conclusion of the study to support the usefulness of the evidence

generated by the study.

While we understand that interest in performing ad-hoc sub-analyses in some

studies, note that they are not viewed in the same way and that these should be

used only to inform future studies. We recommend that you talk to us in

advance about your statistical analysis plan in a Q-Submission.

The recommendations in this Guidance should be used going forward to assist

in the development and submission of new IDEs, IDE Supplements and QSubmissions. We would like to emphasize that this Guidance is not allinclusive. Our recommendations will likely shift and evolve over time as the

field and technology advance. We encourage you to contact us through the QSubmission process with any questions about this Guidance and how it applies

to your studies or devices.
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I've included links to the Final Guidance and where you can submit comments

and suggestions to the Agency regarding the Guidance. I've also provided

links to the pertinent Guidance documents for anyone who would like more

information pertaining to Q-Submissions and IDEs.

At the bottom of the slide is a link to the FDA's 2016 paper in Neuron about

the regulation of neurological and physical medicine devices, which may be of

interest to you as well.

And with that, I will open it up to questions. 

Vivek Pinto: Hey, Heather, This is Vivek Pinto. Thanks for giving the presentation. For the

folks on the Webinar, I'm the Director for Division 5B, the Division of 

Neuromodulation and Physical Medicine Devices.

Just to start off the questions, you know, Heather, could you describe our

organizational unit as an Office and Division and also give some feedback for

the audience about when they submit a review, you know, what should their

expectations be? Like, how does it go through the review process for, let's say, 

Q-Submissions and IDEs?

Dr. Heather Dean: Sure, thanks, Vivek.

So, we're located within CDRH and OHT5, which is the Office of

Neurological and Physical Medicine Devices, which has two Divisions –

Divisions A and B. You know, as you mentioned, you're the Division Director

for Division B – Division of Neuromodulation and Physical Medicine

Devices, which has four teams – two that are focused more on

neurostimulation and two that are focused more on rehabilitation.
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This particular team that that covers many of the BCI devices is on the

rehabilitation side. It's a team of about 10 people. And when a submission

comes in, that is routed to us and assigned to one of the Lead Reviewers. And

a Lead Reviewer in the team – you know, they come from a variety of

backgrounds, engineering and science – you know, especially neuroscience.

And they will then put together a team of experts to review that submission. If

there are detailed biocompatibility questions, they will tap biocompatibility

consultants within the Center, generally, within the Division, to serve as a

consultant on that file. 

If there are detailed questions about sterility testing, we have consultants to 

cover that. We also have our colleagues in the Office of Science and

Engineering Laboratories for many of the questions on the details of the

scientific studies or animal studies.

So, the Lead Reviewer puts together this team of experts to answer your

questions or review the marketing submission or IDE. And then, the Lead 

Reviewer is the main contact with the sponsor – which is that we call anyone

who puts in a submission – the sponsor.

And then that Lead Reviewer is generally the conduit for questions from the

review team to the sponsor. Does that answer your question?

I'm going to go with Yes. And are there additional questions?

Coordinator: As a reminder, if you would like to ask the question over the phone lines, 

please press Star-1 from your phone, unmute your line, and speak your name 

clearly, when prompted. Your name is required to introduce your questions. 
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We ask that you please limit yourself to one question to allow time for all

questions to be addressed.

To withdraw your question, press Star-2. Again, to ask a question over the

phone lines, please press Star, then 1. 

One moment as we wait for any questions over the phone lines.

Our first question over the phone lines comes from (Allison Kuwayama). 

Your line is open.

(Allison Kuwayama): Hi, thanks so much for taking my call, and thanks so much for this

Webinar. This is insanely useful, and I appreciate FDA's efforts in this field.

My question is about biocompatibility. I know that the Guidance document, as

well as the slides, mentioned using (ISO-10993). I just want to know if FDA

is open, based on my understanding of it being a recognized standard, of the

use of ASTM F2901. I think it's -19 is the one that's recognized, and that's the

Standard Guide for Selecting Tests to Evaluate Potential Neurotoxicity of

Medical Devices. Is that one an acceptable standard to use in evaluation of

these devices?

Dr. Heather Dean:That question is really beyond the scope of this particular Guidance document.

I would have to talk to one of those specific biocompatibility consultants that I

mentioned to answer that question.

But if you follow up with, you know, by writing to us, you can reach us either

by writing to the Division of Industry and Consumer Education, or you can

reach out to directly to me. My email address is
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Heather.Dean@FDA.HHS.gov. And you can ask a question any time, and I

will try to get back to you.

(Allison Kuwayama): Awesome. Can I ask one other question? I'm sorry, I can jump back, I'm...

Dr. Heather Dean: Sure.

((Crosstalk))

Dr. Heather Dean: And the other thing I was going to say is to go directly to the biocompatibility

Guidance document, which you've probably already looked at as well.

(Allison Kuwayama): Yes, I have. It just doesn't make any mention of that standard. And I know

that one is recognized by FDA for any neuro-touching devices. So, I just

didn't know that one was one that was acceptable.

My guess – my, just my follow-up question was I didn't quite follow the – or

understand the Right to Reference of one that's applicable. You had

mentioned that one – that if the device is cleared or approved, that they don't

need the Right to Reference Letter. I just I kind of missed the statement. Do 

you mind restating it?

Dr. Heather Dean: Sure.

(Allison Kuwayama): Thanks.

Dr. Heather Dean: So, for example, you might be using – within the indications – a prosthetic

device or surgical tools, and for those we don't need a Right of Reference

Letter.
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But if you are using something that goes beyond the indications – for

example, if an electrode array is cleared for use up to 30 days, and your study

intends to implant this device for longer than 30 days, that is outside of the

indications for use. And it does require a Right of Reference Letter from the

manufacturer.

(Allison Kuwayama): Got it. 

Dr. Heather Dean: Does that answer your question?

(Allison Kuwayama): That's helpful. It does. Thank you so much, Heather. Appreciate your help.

Dr. Heather Dean: Absolutely.

Coordinator: Our next question comes from Thomas Oxley. Your line is open.

Thomas Oxley: Hi, this is Tom. Can you hear me?

Dr. Heather Dean: Yes.

Thomas Oxley: Thank you very much, Heather. That was extremely helpful.

I had a question; I don't know how much information you can provide around

the pivotal trial design, particularly for pivotal trials for Class 3 implantables. 

Numbers are very large.

And I wonder if you've had any discussions internally about general numbers

you're expecting to see in pivotal trials, compared to what you might normally

see from Class 3 implantables?
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And further to that, you mentioned the term, control. Around study design for

a neuroprosthesis control is quite challenging, obviously. So, I wonder if

there's any broad Guidance you can provide on those issues. Thank you.

Dr. Heather Dean: No – great questions. We have not, because these devices can vary so, so

much, and then the patient populations can vary so much. And your ability to

recruit patients can also vary greatly, depending on the indications and the

device itself.

And so, I can't give you a number – a specific number for something like that. 

What I would recommend is that you talk to us early and often in QSubmissions to get an idea what we might expect in terms of, you know, 

patients recruited in order to collect data sufficient to demonstrate the safety

and effectiveness of their device.

You can obviously put in a pre-submission at any time and talk to us and put

in multiple pre-submissions.

Thomas Oxley: Thank you.

Dr. Heather Dean: You're welcome.

Oh, and what was the second part of your question? Remind me again?

Thomas Huxley: You mentioned the term, controlled, in the study design for pivotal, and that's

a bit of a challenge for neuroprosthetics.

Dr. Heather Dean:It is, it is. And again, that that is going to really depend on the device design. 

And we need some scientific evidence that a device is effective for the

indication.
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So, if it's stimulation involved in rehabilitation, say, after stroke, then we

might need that patient population compared to another patient population. 

And we'd have to very carefully look at how that is designed to make sure that

there aren't confounding factors.

I don't think that we could give any general Guidance on something like that. 

We'd have to talk to you in a pre-submission about the details.

Thomas Huxley: Thank you very much.

Dr. Heather Dean: Absolutely. I highly recommend – you know, for things like that, before

starting any study, discuss with us your controls, because the last thing you

want is to collect data and spend a lot of time and money and then find out the

control, you know, has some confounding factors so that we can't tease out the

effect of the device.

Coordinator: We have no additional questions over the phone lines at this time. As a

reminder, if you would like to ask a question, please press Star-1 from your

phone.

Irene Aihie: Thank you. Before I close, Heather, would you happen to have any other

closing remarks while we stand by and see if there are any other questions

before we close the Webinar?

Dr. Heather Dean:I am very excited to see what happens in the next few years in this field. I am

very interested. I'm a neuroscientist by training myself, and I find it incredibly

exciting to see what is coming down the pipeline.
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And I hope that all of you that are working in this field engage with us early

and often. We want to be your partners in making sure that these devices get

to the patients that need them. We do not intend to be a roadblock. We are

here to help you, and we welcome questions, informally and formally.

You can reach out to us any time, and just let us know what you're thinking –

what we can expect. My email is always open for questions. I am definitely

interested to see where this goes in the next few years. So, thank you for being

our partners in all of this.

Irene Aihie: Thank you so much.

Well, it seems like we don't have any more questions, so I'll go ahead and

close. Thank you to all of our participants for your participation and

thoughtful questions.

Today's presentation and transcript will be made available on the CDRH

Learn Web page at www.FDA.gov/training/CDRHLearn by Friday, August

6th.

If you have additional questions about today's presentation, please use the

contact information provided at the end of the slide presentation.

As always, we appreciate your feedback. Following the conclusion of today's

live Webinar, please complete a short 13-question survey about your FDA

CDRH Webinar experience. The survey can be found at the

www.FDA.gov/CDRHWebinar immediately following the conclusion of

today's live Webinar.

Again, thank you for participating. And this concludes today's Webinar. 
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Coordinator: Thank you for your participation in today's conference, you may disconnect at

this time. Speakers, please stand by for post-call.

END