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FDA Webinar: 

Regulatory Advice for Investigators and Sponsors of Neurological Devices and the Path to 

Initiating Human Studies - Wednesday, September 14, 2016

Moderator: Irene Aihie

September 14, 2016

10:00 am ET

Coordinator: Welcome and thank you for standing by. At this time all lines are on a listen 

only mode until the question and answer session. At that time, if you'd like to 

ask a question, you may do so by pressing Star, then 1 and recording your first 

and last name.

Today's call is being recorded. If you have any objections, you may 

disconnect at this time. I would now like to introduce your host for today's 

call, Ms. Irene Aihie. You may begin.

Irene Aihie: Welcome to today's FDA webinar. I am Irene Aihie of CDRH's Office of 

Communication and Education. As part of the FDA's ongoing effort to assure 

patients and providers have timely and continued access to safe, effective, and 

high quality medical devices, we are hosting today's webinar to provide 

investigators, sponsors and new developers with information on the regulatory 

landscape for neurological devices.

This webinar is part of the FDA's partnership and the White House Brain 

Initiative focused on understanding the human brain and uncovering new 

ways to treat, prevent and cure brain disorders.
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Dr. Carlos Pena, Director of the Division of Neurological and Physical 

Medicine Devices in the Office of Device Evaluation here at CDRH will 

begin today's presentation.

He is joined by members of the Division. Following the presentation, we will 

open up the line for your questions related to the information presented in 

today's webinar. Additionally, other center subject matter experts will join the 

team to assist with the Q&A portion of our webinar. Now, I give you Carlos.

Carlos Pena: Thank you, Irene. Good morning to all those on the phone. My name is Carlos 

Pena and I'm the director for the Division of Neurological and Physical 

Medicine Devices and I'd like to welcome you to our first FDA regulatory 

webinar for investigation sponsors of neurological devices.

This is a 90 minute session comprised of a couple parts including a brief 

primer on medical device review and regulation, non-clinical testing, early 

feasibility studies, and best practices on engaging with FDA.

Our goal is to brief all attendees on each of these points, but most important, 

sponsors and investigators obtain a sense of how to navigate the regulatory 

landscape of medical devices so that our landscape is more transparent, 

predictable and efficient and thereby assures patients and providers have 

timely and continued access to safe, effective, and high quality medical 

devices.

This webinar also supports, as Irene mentioned, our support of the White 

House Brian Initiative, which is focused on understanding the human brain.

I'd also like to mention that this webinar is hosted not only by myself, but 

several talented staff in the Division of Neurological and Physical Medicine 
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Devices, one of the newest divisions at the Center for Devices and 

Radiological Health at the FDA.

So at the FDA, the vision of the Center of Devices and Radiological Health is 

that patients in the United States have access to high quality safe and effective 

medical devices of public health importance first in the world.

We take this principle seriously with urgency and we hope to show you how 

serious we are with some hard data at the FDA. A medical device where some 

background is defined as an instrument or apparatus, implement, machine or 

related article intended for use in a diagnosis or cure, medication, treatment or 

prevention of disease or intended to affect the structure and function of the 

human body and does not achieve any of its primary intended purposes 

through chemical action.

And so you might be saying, "Carlos, there are several provisos, addendums, 

clarifications. What really is a medical device?" And in short, if it diagnosis 

treats or prevents disease, it's a medical device.

It also does not achieve this purpose thought chemical action. And one can 

classify a device as a medical device even in the absence of change where the 

device impacts the structure or function of the human body.

We have been engaged in this technology sector some time. And this is a 

favorite slide of mind. Here I show you an array of products with neurological 

implications beginning with neurothrombectomy devices, epilepsy DBS, 

neurodiagnostics, prosthetics, therapeutic devices for migraines and micro 

catheters for the neurovasculature during surgery.
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Many of these products treat diseases or conditions. The goal is not to discuss 

individual data in support of each device, but share with you here that each 

device went through a regulatory path that was in part tailored to the 

individual risk and benefit profile of the device.

And when other products may be targeted for the same indication or used in 

combination, we regularly, often, and without hesitation engage our 

colleagues in other product centers.

Medical devices are classified into class one, two, and three with regulatory 

control increasing from class one to class three. The device classification 

regulation defines the regulatory requirements for a general device type.

And so, for example, most class one devices are exempt from submitting an 

application to the FDA, most class two devices require pre-market 

notification, and most class three devices require pre-market approval.

We provide oversight across the three classes using tools known as general 

and special controls for which we helped communicate to sponsors and 

investigators to help them meet their regulatory obligations.

As mentioned in the last slide, medical devices can be classified into three 

types, two of which are listed here - class two and class three. And these 

higher risk classifications are linked to regulatory submission pathways.

For example, we receive several dozen PMAs each year. These submissions 

are the highest risk and typically require clinical data. These are class three. A 

second pathway is the 510k submission pathway.
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And we receive several thousand each year. They typically do not contain 

clinical data, but are supported by non-clinical data and bench testing and 

review of prior submissions that may have contained these clinical data.

These are typically class two. And, finally, a third regulatory pathway is the 

general submission process, which includes devices that aren't comparable to 

anything on the market and present a low to moderate risk other than other 

types of devices.

Typically, once we have granted a De Novo, that particular product becomes 

the predicate for subsequent products, which can then move along the 510k 

pathway.

And De Novo submissions would be the subject of our next webinar early 

next year. Another question that might arise is when is clinical data needed, 

especially when human studies maybe need to be an issue and are significant 

advance investments by sponsoring investigators, which FDA realizes.

Typically for PMAs, clinical data is needed. For De Novo submissions, 

typically clinical data may be needed, but it may not always be needed. And 

for 510k submissions, clinical data is typically not needed, although there are 

cases where clinical data was submitted.

So you're probably thinking to yourself, again, "Carlos, there are a couple 

provisos, addendums, and clarifiers. How do we really find out what is 

needed?"

And my response is that you can request feedback on any of these questions 

through the use of processes with pre-submission, preferably before starting 
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the study or making any investment into your device technology development 

plan.

And we will return to this shortly when Tim Marjenin reviews best practices 

on how to engage EFDA. One very important step in making sure is making 

sure sponsors and investigators understand the options that are available to 

them to get their product to market and making very clear and transparent the 

regulatory landscape.

Here are several guidance documents that are relevant to neurological devices 

listed in two pre-submission guidance documents that allows for an 

opportunity for early discussion and feedback from FDA to early feasibility

studies designed to (unintelligible) for pivotal clinical investigators and 

expedite the access regulatory pathways for device.

And I'd like to note that the approach to earning feasibility studies will be 

discussed also during this webinar by Erin Keegan and Devjani Saha. All the 

guidances are intended to verify as clearly as possible the considerations that 

should be addressed to hopefully move a product to market and ultimately to 

patients.

And FDA's considering additional guidance. I'm delighted to indicate earlier 

this year we released a draft guidance for public comment, not from 

(unintelligible) focused conducting clinical trials on medical devices targeting 

neurological disease progression and (unintelligible) patient outcome.

A knowledgeable guidance that aims for regulation to keep pace with 

innovations. Many paths to market include selecting simple data about a 

medical device.
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And they usually occur under what's called an IDE or an Investigational 

Device Exemption. Comparable to the drug side of an IND, IDEs allow an 

investigational device to be used in a clinical study in order to collect safety 

and effectiveness data required to support a marketing submission.

Our FDA has 30 days to make a decision about any IDE and we strive to get 

an IDE up and running, because the faster you can get an IDE going safely in 

the United States, the faster you can collect the data that leads to submit and 

marketing the application to get the device to U.S. patients.

And before you get an IDE, we may ask for non-clinical data and Molly 

Ghosh and Dhanya Williams will be discussing with you our non-clinical 

requirements and recommendations next.

But first, I would like to show - share with you how serious we are about 

moving devices to patients. Here is a graph that shows decreasing timelines in 

getting a medical device study up and running.

In FY11, the needed time to get full approval took approximately 400 days.

Fiscal years 2013, 2014 and 2015, we have reduced this time by more than 

half each year with goals and the most recent goal being met in 2015.

And I'd like to stress these appropriate decisions with patient safety of 

paramount importance. One key change has been the interaction and 

engagement with sponsors and investigators.

I will also say that this has not been an easy transition and there has been a 

cost to staff engagement in this effort. And we continue to look for ways to 

make this progress sustainable long-term.
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This webinar aims to help sustain these numbers by helping to educate 

sponsors and investigators and developers and innovators who are there able 

to start up their studies as quickly as possible, understanding FDA's 

expectations to getting these up and running.

And we can approve these studies safely in the U.S. (Unintelligible) messages 

that we want to accelerate getting devices to patients, who desperately need 

them and starting those studies in the U.S. is an important and critical first 

step.

Last, I'd like to mention that our division of neurological and physical

meshing devices is one of the newest divisions in the Office of Device 

Evaluations at the Center for Devices and Radiological Health.

The office is the primary point of the device evaluation for medical device 

sponsors and investigators to engage the agency and we receive submissions 

for investigational studies or market approval in the U.S.

On the bright side called ODE, which there are seven divisions within this 

office, which is the last row and for which neural and physical medicine is 

one. Our division is growing.

And next month we are moving from three branches to five. Neurostimulation 

devices, neurology and psychiatry brands. The neurointerventional and 

neurosurgical devices branches and the physical medicine and rehabilitative 

devices branch.

And you will find no better teams of individuals positioned to safely move 

devices to move to market fastest. I'm a little biased. These five branches take 

on the lion's share of products dealing with neurological devices. And with 
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that, I would now like to turn to the non-clinical testing segment of this 

webinar with Molly and Dhanya.

Molly Ghosh: Thank you, Carlos. Good morning, everyone. My name is Molly Ghosh. I'm a 

toxicologist and lead reviewer in the Division of Neurological and Physical 

Medicine Devices at CDRH.

Today I'm going to talk about the biocompatibility assessment for 

neurological devices. Here is my presentation outline. First, I will provide an 

overview of biocompatibility assessment of medical devices in general.

And then I will discuss some special considerations for neurological devices.

And, finally, I will provide an example of biocompatibility assessment for 

brain implants.

So there are two important considerations for non-clinical review of medical 

devices. One is performance. The question is, is a device going to perform as 

intended?

The other one is about safety. Is our final product going to be biocompatible?

For today's talk, I will focus on the biocompatibility assessment. So what is 

biocompatibility?

Biocompatibility of a medical device referes to the ability of the device to 

receive the desired biological results without causing harm in the body. So it 

depends on the body's response to the device as well as device response to the 

physiological environment inside the human body.

So the next question is, you know, why do we ask for a biocompatibility 

assessment? We don't know always know everything in a final product. Also 
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it is important to know that CDRH regulates medical devices in its final, 

finished form.

It does not regulate the individual materials that are used to replicate the 

device. And you all know that biocompatibility assessment is a critical part of 

medical device safety evaluation. And we recommend the assessment to be 

done on the final stabilized applicable device.

And the reason is, you know, there could be different sources of toxicity from 

a medical device. It could be leachable chemicals or manufacturing residuals 

on the device. It could be potential degradation product or it could be some 

interaction between the leachable chemicals.

Also, the surface geometry, chemistry, and other properties can also adversely 

affect the biological response. So an assessment of potential biocompatibility 

risk from a device include assessing the effects of leachable chemicals from 

the device as well as the assessment of biological discourse to the device's 

properties and geometry of the device.

Also another consideration you need for the device is how biological response 

affects device performance. So ISO 10993 series of standards are widely 

followed for the biological evaluation of medical devices.

There are 20 parts to these standards. Some of the parts are really specific in 

testing guidance, while others are general. ISO 10993 part 1 provides 

guidance on biocompatibility assessment strategy.

It describes the device categorization and then recommends the assessment 

based on the category of the device. So I'd also like to mention here that in 

June of this year, we issued a guidance on the use of ISO 10993 part one.
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And this is actually going to be implemented today. So I will strongly 

encourage you to review the standard, if you are planning any submission to 

FDA. Also I would like to mention about CDRH standard program.

And I provided a link to the guidance document on the recognition and use of 

this consistent standards. So as I mentioned earlier that ISO 10993 part one 

described device categorization.

So biocompatibility assessment, the devices are categorized based on nature 

of tissue contact and duration of tissue contact. So based on the nature of 

tissue contact, the devices are categorized as perfect contacting device, 

external communicating device, and implant device.

These standard duration of tissue contact, the devices are categorized as 

limited contact, prolonged contact, and permanent contact. The limited 

contacted devices are those that the contact is up to 24 hours.

Anything beyond 24 hours up to 30 is considered prolonged contacting 

device. And permanent contacting device has a contact duration longer than 

30 days.

The device categorization actually facilitates the selection of the appropriate 

part compatibility endpoint for assessment. For example, you know, the 

biocompatibility assessment requirement for a permanent implant, like a deep 

breath stimulator, would be a lot more than a surface contacting electrode, 

which will be used for probably less than 24 hours.

So there is really no single endpoint that can predict the biocompatibility of a 

device. The biocompatibility risk from a device would be shot down like some 
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acute systemic toxicity or radiations to some long-term effects like chronic 

toxicity or genotoxicity.

So here is a list of the biocompatibility endpoints that you may need to 

consider depending on the category of the device. And as I mentioned earlier 

that the extent of the assessment depends on the device category.

Now I would like to mention also here that some of the endpoints like 

systemic toxicity and endpoints are, you know, or toxicity endpoints can be 

assessed through a chemical characterization risk assessment approach on the 

final finished device.

For some other endpoints, you may consider testing if the existing data could 

not be leveraged. So that's about from a basic information of the 

biocompatibility of medical devices in general.

Here I will provide some special consideration. You need to think of when 

you are assessing biocompatibility of neurological devices. So here are some 

examples of soft neurological devices.

This is no way a full list of diverse area products that we see. These are just 

some examples. And as we see that they are some base materials we just 

frequently use for this kind of products are listed in parenthesis after each of 

the product categories.

I would like to mention here that most of the time the biocompatibility issues 

that we see actually are not from the base material itself. It can come from the 

manufacturing residuals or some of the processing additives used in during the 

manufacturing of the device.
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And that's the reason we recommend why the assessment should be conducted 

on the final phase device. For example, you all know (unintelligible) is a 

known neurotoxin.

And this is used in some polymer production. So if there is any small 

(unintelligible) in that device, you know, it might cause some toxicity. This is 

just an example.

So there are some special consideration for assessing the biocompatibility of 

neurological devices. As you all know, that the brain is protected by the blood 

vein barrier.

But when you're putting an implant in direct contact with neural tissue and 

function of the blood vein barrier. So there is a need for animal implantation 

testing in relevant neural tissue to assess the neurotoxic effect.

Also, we recommend that any devices in contact with neural tissue and CSF

should be non-pyrogenic, meaning it should not cause any fever response.

There are two sources of pyrogen.

One source is the chemicals from the device that can cause fever response.

And that can be tested by the rabbit pyrogen method. Also there is another 

source called bacterial endotoxin, which can also produce fever response.

And that is assessed through the sterility assessment using that LAL testing.

Also it should be noted that any implant or any devices in direct contact with 

CSF and neural tissue should have endotoxin limit of 2.15 endotoxin even if 

25 or less.
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As I mentioned earlier that, you know, chemical striation risk assessment 

approach could be used in lieu of testing for assessing some toxicity end 

points. But there are some limitations.

And this approach may not be relevant for assessing local tissue response.

Also, you know, this chemical characterization risk assessment approach may 

only be used to assess the potential neurotoxicity of chemicals from neural 

implant, if the toxicological data on that chemicals are available from the 

study (unintelligible) these chemicals were administered through the clinically 

relevant route of exposure.

So here I'm going to provide an example on what other factors are endpoints 

to be considered, if you are assessing the biocompatibility of a permanent 

brain implant.

So the device category is considered a permanent implant with neural tissue 

and CSF and in direct contact with blood. So you need to assess the 

biocompatibility for ISO 10993 part one.

And I have researched some of the endpoints that need to be assessed in 

addition to this general biocompatibility endpoints, neural implantation study 

may also be considered to assess the neurotoxicity due to brain contact.

Also, as I mentioned earlier, the endotoxin limit should not go over 2.15 

endotoxin unique (multiplied) for this type of devices. So also I would like to 

mention that currently there is really no standard protocol for a brain 

implantation study in the ISO 10093 standards.
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There is a brain implantation study protocol being developed, which will be 

included as an annex in ISO 10993 part 6, which is the ISO standard for 

implantation.

But currently the standard, which is available does not have this protocol yet.

Brain implantation study for neurotoxicity assessment. So if you are using a 

passive implant for your study, you might consider small animal models like 

rabbit models.

Other consideration could be separate test and control group, equal number of 

male and female animals in the study, and the inclusion of different time 

points to assess what acute and chronic responses.

Also, our study assessment parameters may include clinical observation 

neurobehavioral assessment, and histopathology to look at neurodegeneration, 

VOCs, and mild neuropathy for the neurotoxicity assessment.

You can also - you may also include some of the systemic toxicity assessment 

endpoints like body weight change, food consumption, chemical chemistry, 

the hematological parameters.

So this is just an example of if you were planning on doing a brain implant 

study. These are some of the points you may want to consider. So, lastly, I 

would like to mention also that, you know, if designed accordingly, your 

animal performance for a functional study can be used to address some 

biocompatibility endpoints.

Our next speaker, Dhanya Williams, will be talking about animal study, but 

here I'm just going to provide you an theoretical example. For example, you 

know, you are developing a new deep breathing stimulator system and you are 
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planning on doing large animal study with the active implant to probably 

evaluate some of the stimulation parameters.

What you can do also that - you can actually design this study to assess some 

of the biocompatibility endpoints like implantation, some of the systemic 

toxicity endpoints.

For example, you may consider including control groups like, you know, 

sham surgical control group to assess the effect of surgery on tissues, because, 

you know, surgery causes tissue trauma.

You might also - you may also consider including a control group with a 

passive implant to look at several - to look at the material mediated effects of 

the implant. Different time points may be included in your study design to 

look at acute and chronic responses.

Also, clinical observation behavioral assessment, histopathology, especially 

seems to look at neurodegeneration (unintelligible) could be included as a part 

of the neurotoxicity assessment.

Also, some of the systemic toxicity could be assessed through clinical 

chemistry, bodyweight change, pathology, etcetera. So that's - I would like to 

mention that if an animal study's designed properly to assess some of the 

endpoints, you may not need a separate biocompatibility study for 

implantation. So I will stop here and then hand it over to Dhanya. Thank you 

for your time.

Dhanya Williams: Hi, my name is Dhanya Williams and I am a biologist and a scientific 

reviewer in our division. This section of the webinar will focus on non-clinical 

animal studies.
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So, first, what is the purpose of conducting an animal study? Animal studies 

are intended to demonstrate the device under study is sufficiently safe for 

early human experience.

For example, to support and IDE application or demonstrate device safety in 

support of a marketing application while incorporating modern animal care 

and use strategies. An animal study is warranted when there are performance 

evaluations or identified risks that cannot be addressed through bench of in 

vitro testing.

For example, the effects of technology or materials on brain function and 

neurotoxicity. Good laboratory practice as outlined in GLP regulations 21 

CFR part 58, applies to non-clinical animal studies to ensure the quality and 

integrity of the safety data. GLP regulations also outline the basic elements 

that should be included in an animal study report for regulatory submission.

Non-GLP studies may be acceptable in some submissions, however, sponsors 

should provide adequate justification as to why GLP provisions were not met, 

how the study deviated from GLP, and why these deviations would not impact 

the study outcome.

For example, if an independent quality assurance individual is not utilized to 

periodically monitor various phases of the study, scientific justification should be provided to 

describe how the functions with the quality assurance unit were performed, in order to ensure the 

validity of the data and that the study was conducted in accordance with assigned study protocol.

Also, please note that it's important to provide a full study report with your submission with a 

complete analysis of your data for review. 
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In this section of the webinar, we're going to be looking at some of the aspects 

that should be taken into consideration when designing a non-clinical animal 

study such as animal model selection, study size and duration and study 

endpoints. 

It is important to plan a study in accordance with the device's indication for 

use and any planned clinical studies. This can really act as a road map for 

designing your animal study to address identified risks and to use procedures 

to conduct the study under clinically simulated conditions, when possible.

When selecting an animal model, it's important to provide scientific 

justification for the animal model that's used. An animal model should 

generally be accepted for the study of the device type.

This may be based on the utility of an animal model for a product class based 

on scientific evidence or literature. It is important to take into consideration 

the clinical relevance of implant or treatment site and understand the possible 

local and downstream responses.

Depending on the device, it may be recommended to use a simulated model to 

assess safety and/or performance. For example, the use of a simulated 

aneurysm for aneurysm devices or a simulated clot for neurothrombectomy 

devices.

There are some expected limitations to the use of animal models. For 

example, the tortuosity of neurovasculature of the animal model compared to 

humans or maximum defect sizes or size limitations due to the physical 

characteristics of the animal.
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It is important to acknowledge or address these limitations. There's a great 

diversity in animal models that are used for neurological devices, ranging 

from rats and rabbits to sheep, swine and canines.

For example, in the past swine have been used for neurothrombectomy

devices and canines and rabbits have been used as flow diverters.

When designing an animal study, study size and duration are important 

aspects to consider.

Studies should include the minimum number of animals necessary to generate 

valid and meaningful scientific data to demonstrate reasonable safety and 

performance. 

It is important to include appropriate treatment and control animals for 

evaluation. This may consist of positive, negative, sham, predicate or 

reference device controls.

Study time points should be scientifically based on known tissue responses or 

risks from the use of your device. Studies should be designed to include 

animal cohorts to evaluate tissue responses over the course of the study based 

on the expected duration of clinical use.

For example, it might be necessary to evaluate both short-term and long-term 

responses for a permanent implant device. When selecting study size, it is also 

important to take into consideration the possibility of animal loss over the 

course of the study.
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Finally, an important aspect of the study design is to include adequate 

endpoints to evaluate safety and performance based on the potential risks of 

the device.

For neurological devices, safety endpoints may include clinical observation 

such as neurological and behavioral assessments, hematology and blood 

chemistry, and upon termination of the study, gross necropsy and 

histopathology evaluations should be conducted.

It should be noted that there are various stains available for evaluation of 

tissue response or neurotoxicity. Also, as Dr. Ghosh mentioned earlier, certain 

elements of biocompatibility testing may be addressed in a well-designed

animal safety and performance study.

Performance endpoints may include device condition following use and 

device specific functional endpoints. Additionally, labeling claims may need 

to be substantiated using the animal study.

When evaluating your device, methods to minimize bias should be considered.

For example, blinding of the study, the use of multiple evaluators, and 

randomization.

It is important to include a thorough description of all procedures in your 

submission for our review, including administration of the anesthesia and 

medication, clinical, macroscopic or microscopic evaluations.

This segment of the webinar is designed to provide a general overview of nonclinical evaluation of biocompatibility and animal studies in support of an IDE 

or pre-market submission and we recommend that you contact our division 

using the pre-submission process to receive specific feedback regarding your 
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device. FDA will review proposed biocompatibility evaluation strategies and 

animal study rationale, design and protocols.

However, please note that data cannot be reviewed through the presubmission process. Additional information regarding the use of the Q-sub 

process will be provided later in this webinar.

There are a number of resources available to provide information regarding 

non-clinical studies. As Molly mentioned earlier, the final biocompatibility 

guidance was published in June of 2016 and additional information regarding 

this guidance can be found in a related FDA webinar, which can be located 

through the CDRH learn link provided at the end of the slides.

The GLP requirements for non-clinical laboratory studies are outlined in 21

CFR part 58 and there is a recognized consensus standard website that 

provides a searchable database for standards recognized by the FDA and the 

extent of recognition.

Finally, a very useful resource is the FDA guidance document website, which 

provides a searchable database for both draft and final guidances including 

some neurological device specific guidances that may provide additional 

information regarding non-clinical testing and animal study recommendations 

for that specific device type.

So that concludes this section of the webinar and thank you very much. Our 

next set of presenters will be discussing the EFS program.

Erin Keegan: Good morning, everyone. My name is Erin Keegan. I'm a biomedical engineer 

and lead reviewer in the division. I'm also one of the early feasibility study 

representatives for the division.
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So we're actually going to switch gears from non-clinical and we're going to 

talk about clinical testing. And Devjani and I will be discussing our favorite 

kind of clinical testing, which are early feasibility studies, which is a kind of 

IDE study.

So first I'm going to go through the definition of an early feasibility study and 

how it can potentially benefit you as a sponsor or investigator. Then I'll go 

through the stages of an EFS pathway to IDE and hit on some of the key 

submission milestones.

Then I'll start going through some of the key EFS principles and some 

examples for our division. And at this point I'll hand it over to Devjani to 

finish up key principles, go through some tips and talk to you about initiating 

your EFS.

So an EFS is a kind of investigational device exemption as Carlos mentioned 

earlier. So it allows you to collect clinical data to support device safety and 

effectiveness. 

So an early feasibility study is a standard IDE, except it generally includes a 

small number of subjects, the device is generally early in development, so 

iterations are expected, and there may be limited non-clinical data and 

enhanced clinical mitigations may be required. 

So it's important to note that EFS is an informal designation. And so you don't 

apply to be in the EFS program. If you have a very novel device and you want 

to get clinical data on a U.S. patient, then we will work with you as part of the 

early feasibility study program.
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So how can an early feasibility study benefit you? So it permits a more 

efficient pathway to U.S. commercialization, because FDA feedback early on 

in your development may improve your development strategy and reduce 

unnecessary testing.

Also data collected in the U.S. patient population as maybe opposed to an 

OUS patient population may be easier to leverage to support later studies or 

marketing applications.

The EFS study itself also enables collect of high quality clinical data. And 

most of the time this will be the first time that the device is put into a human 

patient. 

And so with this data you can optimize your device design or operator 

technique. You can refine the intended use population or non-clinical testing 

plan and it can also help you develop subsequent clinical study protocols.

So now I'm going to go through the stages of an EFS pathway to IDE. And 

these are all just recommended stages, but I'll start with we recommend that 

you reach out to Devjani and I informally.

This can be a phone call. And we're here, we will talk about your device. We 

won't be reviewing anything technical. That comes later, but we'll go through 

the EFS program, help you kind of organize your initial submission.

The next stage, again, this is listed optional, but they really are all optional, is 

to do an informational meeting pre-submission, which is a type of presubmission.

And you can actually find more information about this in the Q-sub guidance.

But these are essentially just a low pressure show and tell situation. You won't 
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receive any feedback from the agency, but it allows you to familiarize the 

review division with your device and clinical indication.

So then next you could submit your initial pre-submission. And this is actually 

outlined, the suggested content is outlined in the early feasibility study 

guidance.

And then I really want to highlight stage four, because the EFS process is 

highly interactive and collaborative. And so it's quite possible that you'll be 

submitting additional pre-submissions as you and the review team work 

through some of the non-clinical testing requirements and even the study 

design of the clinical protocol.

And then finally you submit your early feasibility study IDE just like any 

traditional IDE. And we have 30 days to review your study. So now I'm going 

to go through some of the key principles of EFS as we pulled from the 

guidance document.

Though I highly encourage you to actually read through the guidance 

document. You'll find a lot more information there and I’ll go through some 

examples that may be relevant to our device space.

So the first principle is called Just in Time Testing. And so this came about 

from the concern or I guess motivation that comprehensive testing on really 

early phase devices may add significant costs without return.

Because you could be changing your device a month into your clinical trial 

based on feedback you've been receiving. And so we really want to stress 

doing the right testing at the right time.
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And this should not take the place of informative non-clinical testing. And 

these will be worked out in those additional pre-submission processes between 

the review division and the sponsor.

So some examples could be deferring long-term durability testing given the 

criticality of short-term benefits for devices such as glioblastoma, spinal cord

injury or severe psychiatric disorders this may be appropriate.

You could also limit the use of your device to a controlled setting such as a 

hospital or clinic instead of allowing the patient to take the device home in an 

early feasibility.

This could change testing strategy for electromagnetic compatibility for 

certain electronic based assistive devices. You could also use a small - for a 

small number of devices you may rely on single lot ethylene oxide 

sterilizations versus the full sterility validation.

So this may be applicable for a novel spinal cord stimulation lead.

The next principle I'll go through is the idea of using enhanced risk mitigation 

strategies in your clinical protocol. And so the concern here is that an EFS 

may carry greater unknown risks as compared to traditional feasibility and

pivotal studies.

Because these are just such new devices and we don't have as much 

information to evaluate the risk assessment up front. And so how we handle 

this is build in clinical monitoring right into the protocol.

This could also include more frequent or detailed safety reporting to the FDA 

than you would see in a traditional IDE. And importantly the informed 
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consent should highlight the greater unforeseeable risk and the natures of 

these studies.

Because in the end the patients need to understand that this an early feasibility. So some 

examples could be if you have a stimulation, a stimulation device and you 

may be expecting some adverse events.

The ability to titrate the therapy or turn the device off and revert to standard of 

care could be used. If you have a novel endovascular stroke intervention or 

just a novel surgical procedure, you could consider selecting expert surgical 

sites so that there's control in that aspect.

Finally, if you have completed necessary biocompatibility and sterility, but 

you're still unsure about maybe the procedure or some aspect of the design 

and you want to monitor for infection, you could build that right into the 

protocol by having monitoring of the implantation site and the body 

temperature. So at this point I'm going to turn it over to Devjani to finish up 

the EFS topic.

Devjani Saha: Good morning, everyone. As Erin has mentioned, I'm just going to finish up 

the remaining EFS slide. So one of the pillars of EFS is the ability to leverage 

data from non-traditional formats such as literature or testing from marketed

products or earlier prototypes that you may have.

It is important to understand that if you are considering leveraging data, you 

should provide a detailed discussion of the differences between the leveraged 

data and your proposed device.

These are differences in the materials, the device design as well as the 

manufacturing process. You should also include a strong leveraging rationale, 
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which discusses why, despite these differences, the data can still be used to 

support the safety and effectiveness of your device.

Some examples of leveraged data that we have seen in our division is 

leveraging of biocompatibility endpoints from functional animal studies that 

was discussed earlier in the biocompatibility section by Dr. Molly Ghosh.

Data can also be leveraged from published literature, so for example, with 

adequate justification, it may be feasible to leverage published spinal cord 

stimulation parameters to support stimulation parameters for a novel 

peripheral nerve stimulation.

So another key EFS principle is Timely Device and Clinical Protocol 

Changes. So devices under EFS may be early in development. And it's 

expected that the design of the device may change throughout the course of 

the study.

This highlights the need for timely device and clinical protocol changes.

Changes to the device or clinical protocol may be accomplished through two 

different approaches, the first being contingent approval.

With this approach, device changes that you are anticipating during the study 

can be executed without necessarily additional FDA action, if the proposed 

changes, the supporting test plans, and the acceptance criteria were agreed 

upon in the IDE or IDE supplement.

There's also a broader implementation of the five day notice in EFS IDEs. So 

traditionally five day notices allowed for changes in the device design that 

were not significant as long as it did not affect the safety of the subject.
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It also could not affect the validity of the data or the scientific soundness of 

the trials. These changes were allowed to be made prior to FDA approval, but 

the sponsor would need to inform the agency within five days of actually 

implementing the change.

In EFS, the five day notice is a bit broader, since EFS studies are associated 

with a small number of subjects and don't necessarily aim for statistical 

significance.

So, for example, the sponsor may be able to change the effectiveness endpoint 

to an EFS study as long as these changes don't affect the safety of the study.

We've also seen 5 day notices which include minor changes to device design 

such as ergonomic modifications.

In terms of contingency approval, we haven't seen many of these in our 

division. But some hypothetical scenarios may include the ability to adjust 

simulation parameters and possibly interchange prosthetic device components 

without FDA approval, if the proposed changes have been agreed to during

the review of the IDE or IDE supplement.

So for the next several slides, I'll be presenting some tips that we often give to 

new EFS sponsors. So if you're making device modifications, we highly 

recommend that you record the device modification along with the rationale

for why the modification was made.

You should also record the testing that was completed with each device 

iteration. And you should keep samples of previous generations for leveraging 

in future submissions.
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So, for example, you may be able to leverage some biocompatibility 

endpoints, if your previous generation had identical materials and similar 

manufacturing processes.

If you would like to use test results that were not obtained per standard FDA 

recommendation, we strongly suggest that you provide an explanation for why 

the data is sufficient.

So, for example, if your animal study deviates from GLP requirements, you 

should tabulate each part of the regulation, list how the study deviates, and 

describe how you will still be able to ensure the integrity of the data and 

minimize bias.

The next tip deals with the use of short-term animal studies to support EFS 

initiation of a device that's intended for long-term use. So if you're planning to 

do this, we strongly recommend that you provide supporting evidence that 

short-term results are predictive of long-term safety.

You should also consider applying additional clinical mitigation strategies 

such as longer term follow up. And you can also think about conducting 

additional non-clinical testing such as mechanical integrity testing under 

exaggerated use conditions and perhaps also support your submission with 

computational modeling to support the long-term safety of your device.

Please note that additional long-term animal data may be needed to support a 

larger clinical study. So when do you know that you're ready for an EFS?

Well, it’s generally when you can describe why additional non-clinical testing 

will not be informative and therefore a human study is necessary.
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You can also justify how any leverage information supports your clinical trial 

and you can identify the potential risk and how they will be adequately 

mitigated.

We recommend that you communicate these points to us using a device 

evaluation strategy as described in the EFS guidance. And the link is provided 

in the slide here.

We’re often asked by sponsors, “When is a good time to talk to the FDA 

about EFS?” Well, it's typically after you’ve established your general device 

design, you have an idea of your intended use, and what information you 

would like to gather from the EFS.

And we strongly recommend, that you come talk to us before conducting 

expensive, and time consuming, non-clinical testing. We also recommend that 

you reach out to the division EFS representatives, which are Erin and myself 

to informally discuss the submission strategy.

Our contact information can be found at the end of the presentation. Thank 

you for your time. And now I’ll hand the mic over to Tim Marjenin, who will 

present an FDA engagement and the pre-submission process.

Tim Marjenin: Thank you, Devjani. So, my name is Tim Marjenin. I am the chief of the 

Neurostimulation Devices Branch in the division and I’m going to be covering 

a few key aspects of the Q-sub guidance.

The guidance covers multiple types of interactions. Today we will focus 

primarily on pre-submissions, with also a little bit at the very end of my 

presentation, about risk determinations.
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So, one of the big things that always comes up with regards to presubmissions, is the timeframe for review. And per the guidance, we do try to 

hold a meeting, if you request one, within seventy-five to ninety days when 

we acknowledge receipt.

So we will provide feedback, about 3 days in advance, if you request a 

meeting. You should, generally, plan to meet with us or receive that written 

feedback within about that time frame due to the work load considerations of 

review staff.

So, please budget your time accordingly as you’re planning out how long you 

anticipate various steps in the process to take.

Why engage as early as you can? Well, pre-submissions allow for central 

issue to be identified earlier and we can work with, work through them with 

you as appropriate. Particularly, if you might have some type of novel 

technology or some sort of novel testing.

You can always submit a supplement to get additional feedback if additional 

things come up. Or, if you revised something and you want our feedback on 

revisions.

One of the common issues that we see with regards to pre-submissions, it’s 

actually a fairly common issue across the spectrum of submission types, is ecopy.

You really need to make sure that you comply with the e-copy guidance, 

because, if you don’t, your submission will not be officially logged in, the 

review clock doesn’t start, and nothing else happens.
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I won’t even know that it exists. And so there is an email address here. You 

can direct questions about the e-copy program to that email address.

As far as submission contents are concerned, it’s pretty basic and fairly 

general. Cover letter, background information, necessary information about 

device description, the types of protocols that you’re running, whether it be 

bench or animal clinical study protocols, if there are any specific questions 

related to that background information.

One of the common issues that we see with regards to this is you - not enough 

information is provided up front. So, a few years ago we did an analysis of 

investigational devices exemption letters and we found that the area 

generating the most questions was actually, device description. What the 

device is and does, instructions for use, the hazard analysis.

And this is something that we see across the other submission types. If we 

don’t have enough information to understand the device, we end up asking a 

lot of questions. And, providing complete responses to those questions takes 

your time, and that extends the overall length of the review.

So it’s important to remember, that you as the applicant, know the most about 

your technology, and not the FDA. The more that you can explain the thought 

process when you submit the pre-submission upfront, the more we can focus 

on the substance and give you better feedback.

It’s also helpful to understand the existing landscape as you’re doing this. So, 

please search for and review applicable guidance documents and standards, if 

there are any, such as biocompatibility, which you heard about earlier. As well 

as other things, like software, which applies to a lot of devices that come 

through our division.
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Make sure you explain the relationship of what you are proposing, compared 

to what’s been done in the past. As far as background information, it really is 

okay to err on the sides including more of what you think might be needed.

Just make sure that it’s organized and easy to follow.

And if you intend to cite literature, articles, please provide copies in the 

submission. There is such a thing as providing too much information. It’s 

fairly rare. We don’t need to see circuit diagrams for your devices.

We don’t need to see lines of software code. We don’t need to see a copy of 

the entire grant that you may have submitted to NIH.

It’s good to avoid assumptions. Unless there is an applicable guidance 

document, an applicable standard or another regulatory precedent that you can 

cite, it’s a good idea to identify the most appropriate approach for your needs, 

and to justify it.

For example, not every animal study needs to use a non-human primate 

model. Some other type of model and protocol might be better suited to your 

particular situation. We also see some issues when it comes to specific 

questions. For example, not providing your own proposal for us to review.

It’s not really a great question to say, “What animal should we use?” Or, 

“How large should the sample size be," if you’re talking about a clinical 

protocol. We also get questions every now and then about wanting us to 

review data.

“Does FDA have any comments on the non-clinical test results?” That’s 

something that’s left for the review of the actual marketing submission or an 
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IDE, if that’s the case. When it comes to specific questions, they should build 

on the background information that you’ve provided.

So, rather than saying, “What animal model should we use,” you obviously

proposed one in the submission. “What concerns do you have with our 

proposed animal model?” It’s helpful if you’ve said “Here are some of the 

approaches that we’ve considered. Here is why we think ours is the most 

appropriate for our situation.”

Another example of a good question: “Are the proposed sample size 

calculations method end related elements of the statistical analysis plan 

appropriate for the proposed clinical study?” Again, getting us to comment on 

the approach that you have proposed.

Let’s finish up with a quick slide related to significant risk, non-significant 

risk and basic physiological research, with a focus on when an IDE is not 

required.

An IDE is not required in several different circumstances. For example, if 

there are exempt studies, for the IDE regulations, such as studies of approved 

devices that are used in accordance with your labeling.

Also, certain diagnostic device studies. An IDE is also not required for a basic 

physiological research, which is not for the purpose of evaluating safety or 

effectiveness of the device.

We also don’t need an IDE for practice of medicine when you’re talking about 

care of a specific patient with an approved device. And finally, we don’t need 

an IDE for non-significate risk studies. The IRB can and should be making the 

first cut as to whether an IDE is required.
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However, if you still have questions about that, there is another type of Q-sub, 

referred to as a risk determination request, which is outlined in the guidance 

document.

You can send that in to us and we will evaluate it, and the outcome will be a 

letter saying either that you’re a significant risk, you need an IDE. Nonsignificant risk, you don’t need an IDE, or its basic physiological research, in 

which case you would also not need an IDE.

That concludes my section of the presentation. I’m now going to turn the 

microphone back over to Dr. Pena, who will close out with some remarks.

Dr. Pena: Thanks, Tim. So, a few closing thoughts. Our job at FDA, is to ensure the 

safety, effectiveness and security of a wide variety of medical products.

Including medical devices and neurological devices.

Neuro-technologies represent the merging technology area that we very much 

want to support, and make our nugatory landscape, as transparent as possible.

Along these lines, we encourage industries, sponsors, developers, innovators, 

to consult earlier with the agency, which offers FDA staff the opportunity to 

clarify the data needed to bring safe and effective products to market in the 

fastest way possible.

And most importantly, the faster we are able to evaluate products that are safe 

and effective, potentially, the faster patients (unintelligible) and get the 

products they desperately need.
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And I would like to thank the staff, in the planning, the execution, and the 

presentation of this webinar for FDA that is for this session. On the next few 

slides, we provide a primary point of contact for the Center Device Division 

and Consumer Education as well as additional resources, should you have 

questions.

That is a very good place to start. And, with that, I would like to close the 

presentation portion of this webinar. We are going to take approximately a 

one minute break and then we will open the session to questions and answers.

Thank you.

Coordinator: Momentarily, we will be beginning the formal question and answers session 

of the call. At that time, if you’d like to ask a question, please press Star then 

1, and clearly record your first and last name. If you’d like to withdraw your 

question, you may press Star then 2.

Again, to ask a question, please press Star then 1, unmute your line and 

clearly record your first and last name. There will be a brief moment between 

each question. Thank you, we will be beginning momentarily.

We would now like to begin the question and answer session. Again, to ask a 

question, please press Star then 1 and clearly record your first and last name.

Please try to limit it to one question, per person. If you have additional 

questions, you may re-queue for additional questions. One moment for the 

first question please.

Carlos Pena: Me again. I might take the prerogative as this (unintelligible) ask a couple of 

questions to our staff. One question that we often get, that I’ve often received 

in conferences, and in correspondence, is sort of like, you never ask 1 

question, you ask 3 questions.
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"Is it, is it ever too early to contact FDA? What is the best way to engage 

FDA? And, who should I contact?" And so, I’d like for Tim, to give that 

response, because I think they’re aligned well with those questions going well 

with the best practices to get us started.

Tim Marjenin: Is it ever too early? Well, not really, unless you just have nothing done. So, 

even if you are fairly early on in the process, and this is something that I 

didn’t cover as part of my slides, but the aspect of the Q-sub program is, and 

this was alluded to, in the EFS discussion was, the idea of informational 

meetings.

And those are a great way too for sponsors to familiarize us, FDA, with your 

product, with where you are, where you’re going, what you have, what you 

intend to do. Those are things that, that, even though the timeline outlined in

the guidance is 90 days, it’s something where we can generally have a 

meeting a bit quicker.

Because there really is nothing for us to review at that point. It really is just 

kind of a show and tell. And if we have some off the cuff questions, we may 

raise those during the meeting. And those can be, those can be a good intro to

FDA and which can certainly be followed up with one or more presubmissions for specific clinical and non-clinical protocols, and things like 

that.

The best way to engage is through things like that. Taking advantage of the 

informational meeting, pre-subs, things along those lines. Coming in, trying to 

come in just so you can understand as many of the expectations as you can 

before you get to far down in the process, and you run all these tests, only to 
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learn there at the end that, well, maybe that wasn’t actually what we were 

looking for.

The whole idea is to try and make the process as efficient as possible and to 

make sure that everybody understands the expectations as you’re going 

through the process. And, the pre-submission process is a great way to do that.

And then as far as who to talk to, well, if you happen to see somebody at a 

conference, and you know that they are FDA, you can say hi. We’re friendly 

people. If you have specific questions, and we’re not in a conference situation 

- when you have a contact, here at FDA, let’s say it’s somebody in this 

division, you can send us - you can send us a question.

That individual may or may not be the right person to ask. If so, then they will 

try and answer your question to the best of their abilities, as quickly as they 

are able to, considering their other work. Or, if they are not the right person to 

talk to, they can certainly take it over to, who would be the right person.

And, if you don’t really have a good point of contact, I will throw my name 

out there, as one of the three branch chiefs. Branch chiefs are always a good 

point of contact to, to start with if you have a general sense for where your 

product would fall.

Carlos Pena: One additional question that I think with studies is - you know, one question 

that we get is, "I’m somewhat sure that I think I can go to an EFS study, but 

I’m not quite sure, if I’m really ready to submit. How do I just talk through, 

whether I have an EFS study or something other?" Maybe Devjani and Erin, 

you can respond to that question.
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Erin Keegan: So, I think that’s a pretty common question, and the best thing to do is just to 

reach out to Devjani and I. You can email us and we typically will set up 

some phone calls.

We do those frequently, actually. And, we can discuss your device and what 

you plan, what you want out of this study, actually, is an important question.

So if you want to do a statistically, significant, large study, maybe EFS is not 

right for you.

But, yes, it’s pretty informal. We talked through some principles and we help 

you plan your submission strategy. I don’t know if Devjani has anything to 

add?

Devjani Saha: So, one other thing, is that for EFS, we typically, you know, we try to see 

where the number of subjects are, so there are typically smaller studies. But 

there have definitely been incenses where, you know, you have a smaller 

study, but it may not necessarily be suitable for EFS because there is 

something very similar that you have already, you’ve already submitted as an 

IDE.

So, you don’t need to go through the entire list mitigation because that is 

already kind of with us and we have that on file and it might be easier just for 

you to do a supplement. So, there are certain nuances, and we highly 

recommend that you reach out to Erin and I to discuss those informally.

Carlos Pena: Without any further questions, I’d like to thank the presenters, the meeting 

organizers, and the folks, the many staff that were involved in the execution of 

this webinar. The information is posted online. Folks can take a look and if 

they have questions, following this session, be happy to address questions as 

needed.
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And, we hope to share with you more about upcoming regulatory webinars in 

the neurological and physical medicine devices base, coming up next year in 

2017. As it also relates in support of the White House brain emissions. And 

with that I’m going to turn it back to Irene.

Irene Aihie: Thank you. This is Irene, I hear. We appreciate your participation and 

thoughtful questions. Today’s presentation and transcript will be made 

available on the CDRH Learn webpage at www.fda.gov/training/cdrhlearn by 

Thursday, September 22nd.

If you have additional questions about today’s webinar, please use the contact 

information provided at the end of the slide presentation. And, as always, we 

do appreciate your feedback. Again, thank you for participating and this 

concludes today's webinar.

Coordinator: This concludes todays call. You may disconnect at this time.

END