FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 1

FDA Webinar: Regulatory Overview for Developers and Sponsors of Neurological Devices: 

An Introduction to Humanitarian Device Exemptions (HDEs)

Moderator: Irene Aihie

December 18, 2017

12:00 pm ET

Coordinator: Welcome and thank you for standing by. All lines are in a listen only mode 

until the question and answer session. The question and answer session will 

be at the end of the presentation and only from the phones. At that time, you 

may press star 1 and record your name. Today’s conference is being 

recorded. If you have any objections, you may disconnect at this time. I 

would now like to turn today’s meeting over to Irene Aihie. Thank you. You 

may begin. 

Irene Aihie: Hello and 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 

efforts to assure patients and providers have timely and continued access to 

safe, effective and high quality medical devices, today’s webinar will provide 

developers and sponsors of neurological devices, an overview of the HDE 

regulatory pathway, information about humanitarian use devices, also known 

as HUD, including information about use and the pediatric population, health 

systems for completing an HDE application and we’ll be discussing concerns 

of HDE manufacturing. 

Dr. Carlos Pena, Director of the Division of Neurological and Physical 

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

start today’s presentation. He will be joined by members of the division. 

Following the presentation, we will open the lines for your questions related 

to information provided during the presentation. Additionally, there are other 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 2

subject matter experts here, to join the team, to assist with the Q&A portion o 

our webinar. Now I give you Carlos. 

Dr. Carlos Pena: Good afternoon. Welcome to the FDA seminar on a regulatory overview for 

developers and sponsors of neurological devices. I have an agenda. We will 

be discussing the following - an introduction to humanitarian device 

exemptions, followed by a program overview, HDE basics and pediatric 

considerations; similarities and differences between PMAs and HDEs; HDE 

manufacturing concerns, a risk/benefit analysis and a few closing remarks. 

And then as Irene mentioned, the Q&A session will follow. 

This session is sponsored in part, by staff across the agency. And I’m very 

grateful for all the staff who have contributed to this event. At CDRH, our 

vision is that patients in the US, have access to high quality safe and effective 

medical devices of public health importance, first in the world. For some 

background, a medical device is defined as an instrument intended for use in 

the diagnosis or cure, mitigation, treatment of and prevention of a disease or 

intended to affect the structure or in function of the human body. And does 

not achieve any of its primary intended purposes through chemical action. 

And we can classify a device as a medical device even in the absence of 

claims, when a device impacts the structure and function of the human body. 

So you’re probably saying, Carlos this is quite a lot to remember. But as a 

take home message, if the device typically diagnoses, prevents or treats a 

disease, it may very well be a medical device. 

Now we have been engaged in this technology sector for some time and this is 

a favorite slide of mine. Here I show you an array of products with 

neurological indications, beginning with a neuro-diagnostics device, deep 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 3

brain stimulation devices to surgical kits, catheter systems, stent-assisted coils 

and neurological microcatheters during surgery. 

Many of these products treat a disease or condition and the majority of 

products will authorize for marketing, under the humanitarian device 

exemption or HDE pathway. 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 or 

in this case of HDEs, probable benefit of the device. And you’ll learn a little 

bit more about different aspects of this regulatory pathway. 

I would also like to note, as an intro, that medical devices can be categorized 

into a number of types - including four which are listed here. The Class 2 and 

Class 3 descriptions are high risk classifications that can be linked to 

regulatory submission pathways. For example, we receive several dozen 

PMAs each year. These submissions are the highest risk and require clinical 

data. These are class 3. Another pathway is 510(k) submission. And we 

receive several thousands each year. And 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 clinical data. These are class 2. 

And a third regulatory pathway is a de novo submission process which 

includes devices that aren’t comparable to anything on the market and present 

a lower risk than other types of devices. Typically, once we’ve granted a de 

novo, that particular product becomes the predicate to subsequent products, 

which can then move along the 510(k) pathway. 

And the focus of this presentation, HDEs, are medical devices that are 

intended for diseases or conditions that affect small, rare populations. So as 

I’ve just noted, there are a number of regulatory pathways to bring a device to 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 4

market. And for a more recent paper that FDA published last year, Neuron, 

we show several of those pathways, such as the pre-market approval pathway, 

the pre-market notification or 510(k) pathway. And at the lower half of the 

slide, the HDE pathway, which Katie will be discussing shortly. 

We received a number of HDEs across the division. And here I show one last 

slide on the organization of our division in the pre-market side review, and a 

distribution of products across each of the branches as we now delve deeper 

into the HDE process. And I turn to Ms. Katie Chowdhury, from our HDE 

staff. 

Katie Choudhury: Thank you Carlos. My name is Katie Chowdhury and I am a biomedical 

engineer in the Office of Orphan Products Development. I’m going to 

provide an overview of the Humanitarian Use Devices or HUD programs. Per 

the definition outlined in Title 21 of the Code of Federal Regulations or CFR, 

under Section 814-3N, a humanitarian use device is a medical device intended 

to benefit patients in treatment or diagnosis of a disease or condition, that 

affects or is manifested in not more than 8000 individuals per year in the 

United States. 

In 1990 Congress established the HUD designation in HDE marketing 

pathway program. This program was created to encourage the development of 

devices for disease - rare diseases or conditions. Congress recognized the 

small market would create an economic disincentive for device development 

for rare diseases. Traditionally, in order for a device to enter the US market, 

there has to be a reasonable assurance that the device is safe and effective. 

Under the HUD HDE pathway, the sponsor is exempt from having to 

demonstrate device effectiveness and needs to demonstrate the device is safe 

and provides a probable benefit to the patient. 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 5

Therefore, the HUD HDE program is an alternative pathway for devices 

intended for rare diseases or conditions, to enter the US market. There is a 

two step process if the sponsor wishes to get their device commercialized in 

the United States, through the HUD HDE marketing pathway. First, a sponsor 

must submit a HUD designation request, and receive approval from the Office 

of Orphan Products Development. Second, once the HUD designation is 

granted, the sponsor submits their HDE marketing application to either the 

Center for Devices and Radiological Health or sometimes, if the device is a 

biologic, to the Center for Biologic Evaluation and Research. 

We have provided the Web site link on this slide if you wish to gather 

additional information on how to get a HUD to market. In order to be 

considered for an HDE, a sponsor must first submit a request and receive a 

HUD designation from the Office of Orphan Product Development, as 

previously described. The submission must include one paper copy, the 

original, and one eCopy. The request should contain a cover letter. This 

should request that OOPD consider the device for a HUD designation for a 

rare disease or condition or an orphan subset of a disease or condition. 

The HUD request should describe the disease or condition that the device 

intends to treat or diagnose. You should also provide a proposed population 

estimate. This is a calculation of the number of patients affected or 

manifested with a disease or condition in the United States per year. The 

request should tell us how the device - about the device and how it is used. 

This should include a written description of the device, including engineering 

diagrams, as well as a scientific rationale supporting use of the device. 

Please include all relevant pre-clinical, clinical and/or proof of principal data 

pertaining to the device. And finally, the request should include supporting 

documentation with applicable references, demonstrating that the device is 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 6

designed to treat or diagnose a condition or disease or orphan subset that 

occurs in not more than 8000 individuals per year in the United States. 

We have a guidance for HUD designation that can be located using the 

following link, for more information on what to include in your application. 

OOPD reviews each request in a specific consistent manner. First, we 

evaluate the disease or condition that device is intended to treat or diagnose, 

based upon the device’s functionality. Second, we consider the target 

population that may benefit from the use of the device. 

Please note that we may broaden the requested designation if we determine 

that the device may be used to treat or diagnose people, more people with that 

disease or condition. The caveat here is that the entire population with the 

disease or condition, must not be more than 8000 individuals per year. If the 

target population is over 8000, a sponsor may still obtain a HUD designation 

if they can explain why the population is an orphan subset. 

OOPD conducts the HUD designation request within 45 calendar days, and 

then issues the sponsor a decision letter. OOPD may approve, disapprove or 

request additional information during our review. Approval means that the 

device is designated for the disease or condition that occurs in not more than 

8000 patients per year. Please be aware that disease or condition that is 

approved and receives the HUD designation may not be the one requested by 

the sponsor, if the device may treat a broader or more defined disease or 

condition. 

After an application receives HUD approval, they have the ability to submit 

an HDE to CDRH receiver. We disapprove a designation if we determine that 

the population exceeds 8000 patients per year. For purposes of HUD requests, 

the pediatric population is defined as those younger than 22 years of age. This 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 7

includes the patient’s 21st year of life. Generally, OOPD will designate the 

entire population, both pediatric and adult, if the population estimate of the 

disease or condition affects or is manifested in not more than 8000 patients 

per year, in the United States. 

However, if the overall population exceeds 8000 patients per year, a sponsor 

may pursue a pediatric population if that is not more than 8000. That 

concludes my talk and I am now going to pass it onto Anupama. 

Dr. Anupama Govindarajan: Good afternoon. I am Anupama Govindarajan. I am a lead 

reviewer in the Division of Neurological and Physical Medicine Devices. 

And today I would like to discuss with you the basics of HUDs, HDEs and 

their pediatric considerations. The diagnosis of a rare disease or condition can 

be a devastating consequence for the patient and their family. Only a portion 

of 7000 known rare diseases have approved treatments in the United States. 

By definition, rare diseases or conditions occur in a small number of patients. 

As a result, it has been difficult to gather enough clinical evidence that the 

FDA standard of reasonable safety and assurance. As a result, it was 

uncommon for medical devices for rare diseases or conditions, to be legally 

marketed in the United States. HUD - an HUD is a medical device intended 

to benefit patients in the treatment or diagnosis of a disease or a condition that 

affects or is manifested in not more than 8000 individuals in the United States, 

per year. 

HDE - Section 520M of the Federal Food & Drug Cosmetic Act of, the FD&C 

Act, an HDE is a marketing application for a HUD. An HDE is exempt from 

effectiveness requirements of Sections 514 and 515 of the FD&C Act and it’s 

subject to certain process for use restrictions. There are two steps to get an 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 8

HDE to market. Step one, first the applicants must obtain a HUD designation 

from the FDA’s Office of Orphan Products, referred to as OOPD. 

Step two, after the device is designated as a HUD, the applicant then submits 

the HDE application to the proper FDA review center. Either the Center for 

Devices and Radiological Health, CDRH, or the Center for Biologic 

Evaluation and Research, CBER, depending on which center regulates the 

device. A device is eligible for review in an HDE application if it meets two 

criteria. First, OOPD must designate the device as a HUD. And second, they 

cannot be a legally marketed device for the same disease or condition granted 

under another regulatory pathway that is pre-market notification, pre-market 

approval or the de novo path. 

The approval threshold for an HDE, is based on two factors - the first is a 

reasonable assurance of safety. Note that the law that created the HDE 

program, did not change the regulatory standard for safety. In other words, 

the safety button is the same for both (PME) and HDE devices. Reasonable 

assurance of safety consists of not posing an unreasonable risk of illness or 

injury to the patient. The second factor is specifically what was addressed in 

the law that created the HDE program. 

Specifically, the law exempted HDE devices from demonstrating a reasonable 

assurance of effectiveness and instead, requires demonstration of probable 

benefit. This difference in determination of effectiveness is the key difference 

between the (PME) and HDE application. The basis to approve an HDE is the 

demonstration that the use of the device or its probable benefit outweighs the 

risk of injury or illness from its use. This also takes into account 

considerations whether other available options are available as well as their 

respective benefits and risks. 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 9

What these other devices are already marketed for the similar indication. The 

FDA will only consider HDE applications if there is no comparable device 

available to treat or diagnose the disease or condition, unless the comparable 

device is also approved under an HDE or is still in the testing phase under an 

investigational device exception or the IDE. Comparable device does not

necessarily mean identical. 

If the indications for use, technological characteristics and patient population 

are all the same, FDA may consider the device comparable. The FDA has 

issued a final rule requiring sponsors of medical device applications to submit 

data on pediatric patients as a condition of approval. 

We will now discuss the content of an HDE application. Every HDE 

application should include the following - a copy or reference to the approved 

HUD designation letter. 

The applicant should provide a written explanation of why the device is not 

otherwise available, and a statement that no comparable device is legally 

marketed. The application should include descriptive information about the 

device, such as a device description, including discussion of all device 

components and accessories, and how they work; design drawings and 

specifications, and a listing of the materials of use. 

The application should include a statement of the proposed indications for use. 

This should be consistent with the HUD designated disease or condition 

referenced in OOPD’s HUD designation letter. The bulk of the submission 

will consist of the valid scientific evidence to support the safety and probable 

benefit of the device. This evidence may include a variety of information and 

data sources, such as bench testing, animal testing and all clinical evidence. 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 10

As a conclusion summary of this valid scientific evidence we ask them to 

explain why the probable benefit outweighs the risk of use of the device. 

The HDE application should also contain manufacturing and submission. 

Note that the device must comply with the quality system regulation reference 

in 21 CFR Part 820. 

The amount to be charged for the device as well as a statement indicating that 

the cost of the device does not exceed the cost of the device in such 

development for application and distribution. Sponsors can also apply to 

profit off the devices if the device is intended to treat pediatric patients or if 

the device occurs in such low numbers that its development would be 

impractical or impossible. 

The application should include the physician labeling and if applicable, the 

patient labeling. The labeling for an HDE must contain a statement that the 

device is a humanitarian use device and that though the device is authorized 

by federal law, the effectiveness of the device for the specific indication has 

not been demonstrated. The clinical evidence submitted in the HDE, should

preferably include summaries, conclusions and results of all clinical 

experience or - of investigation. The information should include evidence that 

supports both the safety and the probable benefit. 

We now discuss the possible clinical study limitations in HDE applications. 

The clinical evidence submitted in the HDE should preferably include 

summaries, conclusions and results of all clinical experience or investigations. 

The information should include evidence that supports both the safety and the 

probable benefit. FDA recognizes that there are limitations and challenges in 

the collection of relevant clinical evidence for an HDE device. 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 11

Because HDEs are limited to patient populations with a rare disease or 

condition, it’s maybe challenging to find and recruit these patients into a 

clinical study. This may lead to smaller sample sizes in a perspective clinical 

study. And second, because there is no available comparable device for the 

same indication, these studies may lack an active control and/or 

randomization. 

If you are designing a clinical trial for an HUD HDE device, we strongly 

encourage you to discuss the protocol with us, in a pre-submission, so we can 

help provide feedback on the most appropriate clinical study, considering the 

limited population and appropriate benefit and risk measure. Pediatric 

requirements for an HDE - in January 2014, the FDA finalized its guidance on 

pediatric information required from sponsors of medical devices, including 

HDE sponsors. 

FDA defines pediatric populations as including neonates, that is from 0 to 28 

days; infants, less than two years; children, 12 to 2 years of age; and 

adolescents, under 21 years of age. The Food & Drug Administration Safety 

and Innovation Act (unintelligible) Section 515a, calls for two pieces of 

information from each device applicant. A description of any pediatric 

subpopulations that suffer from the disease or condition that the device is 

intended to treat, diagnose or cure. 

The caveat is that such information must be readily available and addition 

intended to prevent companies from needing to extensively seek out none of 

the (patient). Until the number of affected pediatric patients. A limitation of 

HDE approval is with the approved labeling, the device must clearly identify 

the device as an HUD, it must state that the effectiveness for that indication 

has not been demonstrated. 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 12

The labeling must identify the pediatric population if the HDE was approved 

for a pediatric specific-indication. I will now hand this talk over to (Kelly 

Ann), who will talk about PMAs and HDEs. 

(Kelly Ann Watratich): Thanks Anu. Good afternoon. My name is (Kelly Ann Watratich). 

I’m a biomedical engineer and lead reviewer in the Division of Neurological 

and Physical Medicine Devices. If you’ve submitted a PMA to FDA in the 

past, then you may be familiar with some of the requirements and regulatory 

aspects that are also (unintelligible). However, there are significant 

differences in the HDE regulations and review process that should be 

highlighted and considered before submitting an HDE. We’ll set them to 

(unintelligible) describing the similarities and differences. 

On this slide is a table showing a general overview comparing and contrasting 

PMA and HDE review paradigms. Firstly, the indication for use in the HDE 

is limited by the indications for which a sponsor obtains a humanitarian use 

designation. The process previously described by Katie from the Office of 

Orphan Products Development. Secondly, the law exempts HDE devices 

from demonstrating a reasonable strength of effectiveness, and instead, 

requires demonstration of probable benefit. 

This difference in determination of effectiveness is a key difference between 

applications for pre-market approval, PMAs and HDEs. The review 

timeframe also differs between HDE and PMA submissions, with HDE 

decisions determined typically within 75 days. The timeframe of a PMA 

depends on whether it requires a panel that can be between 180 to 320 days. 

After approval, HDEs may only be used in facilities with IOB oversight. And 

unlike PMAs, HDEs may not be sold for profit, except for in certain 

circumstances. The next few slides we’ll delve into a little more detail 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 13

between these similarities and differences. Slide 30 steps through these 

similarities. Both PMA and HDE submissions, undergo an initial 

administrative review within the first 30 days of receipt, known as the filing 

review. The filing of an HDE means that the FDA has made a threshold 

decision that the application is sufficiently complete to permit substantive 

review. 

Both PMAs and HDES may be submitted for modular review. A modular 

PMA or HDE is a compilation of sections or modules submitted at different 

times, but together become a complete PMA application. The modules may 

be separated into specific topics, such as pre-clinical, clinical and 

manufacturing. FDA intends the modular review approach to provide a 

mechanism by which applicants may submit pre-clinical data and 

manufacturing information for review, while still collecting, compiling and 

analyzing the clinical data. 

Therefore, a modular PMA is a compilation of sections that over time will 

complete an application. The modular approach also allow applicants to 

potentially resolve a deficiency noted by FDA earlier in the review process, 

than would occur with a traditional PMA application. Quality system 

regulations or QSR, apply to both PMAs and HDEs. However, we primarily 

focus on those manufacturing practices that the agency deems most relevant to 

the safety of the device. 

After approval of both PMAs and HDEs, several documents are publicly 

posted, including a detailed summary of the data on which the approval or 

denial decision is based. However, the name of those summaries differ and 

reflect the level of data required for the submission type. The summary of 

safety and effectiveness data or the FSED, are posted for PMA approval. 

Summary of safety and probable benefit or SSPD, are posted after HDE 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 14

approval. Also after approval, both PMA and HDEs have some similar post 

market that requirements, such as potential completion of a post approval 

study, as well as submission of annual report. 

HDE amendment supplements and reports, are generally subject to the same 

regulations as those for PMAs. Now that we’ve gone through some of the 

similarities, here are some key differences that make HDEs unique and are 

important for you to note before submitting an HDE. The first important step 

and difference between PMAs and HDEs, has been said a few times before, 

but you must demonstrate that the intended patient population of the device 

does not exceed 8000 in the US per year. 

User fees for HDEs, are waived under the Medical Device User Fee and 

Modernization Act of 2002 and have been reauthorized and amended by the 

Medical Device User Fee amendment of 2007. As previously noted in the 

table describing the differences, HDEs are exempt from demonstrating 

effectiveness and should demonstrate probable benefit. In demonstrating 

probable benefit, the sponsor should consider including an explanation of why 

the probable benefit to health from the use of the device, outweighs the risk of 

injury or illness from its use, taking into account the probable risk and benefits 

of currently available devices or alternative forms of treatment. 

(Vaccination) can be (supported) by clinical experiences or investigations 

whether adverse or supported, that are reasonably obtained and that are 

relevant to the assessment of the risks and probable benefit of the device. 

When an HDE is approved, the device is considered unclassified while a PMA 

applies the class 3 devices. And as long as the HUD is being studied for 

indications and its approved labeling, the HDE is not subject to IDE 

requirements because the - I’m sorry. Excuse me. The HUD is not subject to 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 15

IDE requirements because the HUD is a legally marketed device and can 

therefore be lawfully shipped without an IDE. 

However, other clinical investigations require requirements that will apply 

including IRB approval and protection of human subjects, including informed 

consent and if applicable, additional safeguards for children. Once approved, 

HDEs also have several post market limitations that differ from PMAs. HDE 

devices require (IRB) approval before being used in a facility. As Anu 

previously mentioned as well, the HUD labeling and materials may include 

the phrase FDA approved, similar to PMAs. 

Also similarly, HDE labeling and materials, must be truthful and not 

misleading. But it should also include a statement clarifying that effectiveness 

has not been demonstrated. HDEs may not be sold for profit, except in certain 

circumstances. An HUD is only eligible to be sold for profit, after receiving 

HDE approval if the device meets the following criteria. The device is 

intended for the treatment or diagnosis of a disease or condition that occurs in 

pediatric patients or in a pediatric sub population and such device is labeled of 

ruse in pediatric patients or in a pediatric subpopulation in which the disease 

or condition occurs. 

Or the devices is intended for the treatment or diagnosis of a disease or 

condition that does not occur in pediatric patients or that occurs in pediatric 

patients, in such numbers that the development of the device or such patients, 

is impossible, highly impracticable or on faith. If an HDE approved device 

does not meet either of those eligibility criteria, the device cannot be bought 

for profit. 

HDE applicants whose devices meet one of the eligibility criteria in which to 

sell their HUD for profit, should provide adequate supporting documentation 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 16

to FDA in an original HDE application, to demonstrate to FDA that the HUD 

meets those eligibility criteria. To continue with some additional differences 

between PMAs and HDEs, HDEs cannot be approved once a comparable 

device with the same indications for use, is marketed through a PMA or 

510(k). In contrast, there may be multiple PMAs or 510(k)s approved or 

cleared for the same indications for use. 

Compassionate use provisions may also be applied to HDE devices. Patients 

may have access to investigational devices that have not received FDA 

approval or clearance for patients for whom the treating physician believe the 

device may provide a benefit in treating and/or diagnosing the disease or 

condition. And if you happen to have an HDE, you can also transition this 

HDE into your PMA. A PMA may be submitted if you’re seeking to make a 

profit from an HDE device or if you’re seeking a different indication that 

might be assessed in more than 8000 individuals per year. 

Please note that when submitting a PMA for an HDE device, for a different 

indication for use than previously approved in an HDE, the effectiveness level 

will shift to the PMA review paradigm, requiring you to provide information 

that demonstrates reasonable assurance of effectiveness. This may include 

additional bench, non-clinical and clinical data. And as I previously 

described, you may collect safety and effectiveness data to support a PMA or 

an HDE approved indication, without an IDE. 

While the work is done to collect such safety and effectiveness data to support 

a PMA, constitutes a clinical investigation, FDA considers the sub data 

exempt from the requirement of an IDE, as long as the (HUD) is used in 

accordance with its approved indications. This concludes our discussion on 

the similarities and differences between PMAs and HDEs. I’ll now pass the 

presentation onto Matthew Krueger. 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 17

Matthew Krueger: Good afternoon. I’m Matthew Krueger and I’m the Branch Chief for Physical 

Medicine, Orthopedic Neurology and Dental Devices in the Division of 

Manufacturing and Quality in CDRH’s Office of Compliance. We are 

responsible and tasked for reviewing the manufacturing information both for 

PMA submissions and for HDE submissions to the agency. We’ll talk a little 

bit today about manufacturing related submissions. That includes original and 

modular HDE submissions; how preapproval inspections fit into that briefly; 

and then we’ll talk about some other submissions to the agency, including site 

change supplements and 30 day notices. 

As discussed and mentioned by (Kelly Ann), there are many similarities 

between PMA submissions and there are also some differences between HDEs 

and PMA submissions. So we’ll talk a little bit about those. Some of the 

similarities relate to the information that you need to submit. So for both 

PMAs and HDEs, manufacturing information is required and the same 

information is required in each of those submissions. There’s not a specific 

HDE guidance, but there is a PMA guidance relating to the required 

information, manufacturing information to be submitted in a PMA supplement 

and we’ll refer to that. There’s a link later on in the presentation to that 

guidance. 

Manufacturing changes also require a submission to the agency. Those can be 

a manufacturing site chain supplement or again, a 30 day notice. The 

differences that you encounter, relate to the timeframe. HDE review 

timeframes are generally shorter than they are for PMA. For the information 

relating to PMAs or for additional information relating to PMAs, we did have 

a PMA webinar that was held on July 26th, that you can refer to for additional 

information relating to what should be submitted as manufacturing 

information. 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 18

In the submissions there is a chart here on the slide which shows sort of a 

comparison and contrast and review timeframe. You know, our goal for 

originals and site change supplements, is 75 days versus 180 for a PMA. As 

many of you know, when that relates to and when that includes is a 

preapproval inspection, that often is a very tight timeframe in order to get a 

preapproval inspection done. 

As it relates to modular submissions, the agency has the same 90 day review 

timeframe for a module. That’s something that you obviously would submit 

before you submitted your clinical data and the Office of Device Evaluation 

started reviewing the clinical data. And then in 30 day notices it’s the same 

timeframe - 30 day notices are submitted when you make a manufacturing 

process change that could affect the safety or effectiveness of the device. 

This slide shows a link to the relevant guidance’s. The same manufacturing 

information that you would submit in a PMA, you would also submit in an 

HDE. So frequently the guidance documents are either written in parallel or 

referred to, in order to give people an idea of what information we would be 

looking for, in a submission so the two guidance’s that are listed here in a 

quality system information for certain pre-market application reviews, 

guidance for industry and FDA staff is one that you would look to when 

you’re submitting an original HDE or the modular manufacturing information. 

It can also be helpful in referring to that for a manufacturing site change 

supplement, using only the manufacturing portion of the information that’s 

required in that guidance document and not necessarily, having to submit the 

design information for a site change supplement. So that can be very useful 

for those kinds of submissions. And then there is a separate 30 day notice and 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 19

135 day pre-market approval supplement. And the 75 day humanitarian 

device exemption supplement for manufacturing methods or process changes. 

And that is helpful in explaining what needs to be submitted as well as what 

types of changes we would look for in a 30 day notice. I’ll now turn it over to 

Greg Kittlesen. 

Dr. Gregg Kittlesen: Thank you Matthew. At this point now I’ll introduce myself. I’m Gregg

Kittlesen, a reviewer in the neuro-diagnostics, neurosurgical devices branch. 

We’ll be looking here at approved HDEs in our division and we see approved 

neurological HDEs include stents, embolics, and balloons used in neurological 

endovascular treatments; a neurosurgical device used to create arteriotomies 

during intracranial vascular bypass procedures; and neuromodulation devices. 

So examples of clinical trial designs for neurological devices, many trial 

designs have been used to gather safety and probable benefit evidence, which 

supported approval of neurological device HDEs. Often prospective 

multicenter single arm non-randomized trial designs have been used. Study 

size patient numbers have been determined depending on the proposed 

indications for use. 

Some indications for use address very small patient populations. Study 

duration and frequency of patient follow up are dependent on the safety 

questions under study and published medical treatment guidelines or common 

practice. Some examples of adverse events that may be observed in clinical 

trials of neurological devices include headache, respiratory problems, stroke, 

nausea, hypotension and shortness of breath. Neurologic death, major 

debilitating stroke, and stroke are considered severe adverse events. 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 20

Examples of probable benefit data that have been observed in clinical studies 

of neurological endovascular treatments include: aneurysm occlusion rate 

defined in this example as 100% or near complete occlusion at a pre-specified 

time point; observed adverse events and associated rates of adverse events; 

and favorable clinical outcome defined in this example as specific measures of 

functional independence and disability, again at a pre-specified time point. 

And now we’re going to turn this over to our Deputy Director, Michael 

Hoffman. 

Michael Hoffman:Thank you Gregg. As Gregg mentioned, my name is Mike Hoffman. I’m the 

Deputy Director for Regulatory Policy in the Division of Neurological and 

Physical Medicine Devices. So I’m going to provide a few notes on the post 

market activities for HUDs and HDEs. So one of the key differences as 

(Kelly Ann) noted earlier in the presentation, is the need for IRB approvals 

after approval of an HDE. So after HDE approval, the device may be only 

used under IRB approval, after IRB approval has been obtained for use of the 

device at a clinical site, for the FDA approved indication, except for 

emergency use situations. 

An HUD used in a clinical investigation is considered to be for investigational 

use whether or not the device is used for the HDE approved indication. Such 

investigational use is subject to the same requirements that apply to all FDA 

regulated clinical studies, including protection of human subjects and 

institutional review boards. If the HUD is being studied for use other than its 

approved indication, the IDE regulations also apply. The HDE holders are 

responsible for insuring that an HUD approved under an HDE is administered 

only in facilities having IRB oversight and acting in accordance with the 

agency’s regulation, governing IRBs. 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 21

IRBs are responsible for initial and continuing review of the HUD. Initial 

review of a HUD must be performed at an IRB’s convening meeting. But 

please note that an IRB may give blanket approval for the use of a particular 

HDE device at an institution, or it may be given approval on a case by case 

basis. Also worth noting is the pediatric advisory committee, which conducts 

periodic annual review of approved HUDs labeled for pediatric patients that 

are allowed to make profit. 

The pack insures that the HDE remains appropriate for the pediatric 

population for which it is approved. The FDA’s Office of Pediatric 

Therapeutics under the Office of the Commissioner, coordinates the review. 

The key information that should be presented to the pack, include medical 

device reports or MDRs, that are received since the approval, as well as other 

relevant safety information. They should also include a summary of any post 

approval studies, as well as a summary of relevant peer reviewed literature 

published since approval. 

A key review question during the review is does the probable benefit in this 

profile of the device for the pediatric population, continue to support the HDE 

for which the exemption was granted? For more informatic about the 

pediatric advisory committee, please see the Web site at the bottom of the 

slide. Similar to - as (Kelly Ann) noted, there are also annual reports for 

HDEs similar to PMAs, however there are additional elements of the annual 

reports for HDEs that also need to be addressed. 

Some of those key differences include information to support the continued 

qualification of the HDE, namely the updated annual incidents assessment and 

an explanation of why the device would not be available, unless an HDE were 

granted and as statement that no other comparable device is available to treat 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 22

or diagnose the disease or condition, other than another HUD approved or 

HUD approved under an HDE, or a device that’s under an approved IDE. 

You should also include an updated explanation why the probable benefits to

help outweigh the risk of illness or injury from its use, take into account the 

probable benefits and risks of currently available devices or alternative forms 

of treatment. You should also include an updated amount to be charged for 

the device and if it is greater than $250.00, you should provide a report by an 

independent certified public accountant or an attestation by a responsible 

individual, of the organization. 

Also included is the number of devices that have been shipped or sold since 

the initial marketing approval. And if greater than 8000, you should provide 

an explanation and estimate of the number of devices that are used per patient. 

Finally, information should also include the clinical experience of the 

approved device, including any safe information that is known or reasonably 

to be known, by the applicant, as well as any medical device report that is 

filed under 21 CFR 803. As well, you should provide a summary of any 

changes made to the device in accordance with the supplement submitted 

under 21 CFR 814.108. 

As noted in previous slides, post HDE approval does require assessment of 

use annually, to determine that the device is still eligible for the HUD and 

HDE programs. However, we recommend that manufacturers do this 

annually, not only to satisfy FDA requirements, but to also see what 

information is available on the use of the device, to look to the future and if 

warranted, look at ways to explore new or expanded indications or other 

regulatory pathways for the approved indications such as a PMA. 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 23

There are examples of HDE devices that have subsequently been approved 

under a PMA in the future, after the HDE population grows beyond the 8000 

incidents or more often, the expanding - expanding the HDE indication after 

further studies. Additionally, some issue are converted to PMAs after 

manufacturers seek to remove some of the limitations that are on the HDE 

program. It is possible to use the HDE as a process and stepping stone toward 

expanding indications after further evidence gathering. 

However, as noted, the regulatory bar is higher for PMAs, thus more evidence 

is needed to support the PMA compared to an HDE. If you are looking to use 

an HDE as an initial step, or if you are exploring ways to expand your 

currently approved HDE into other indications and potentially, a different type 

of regulatory pathway, such as a PMA or a de novo, please come talk to us by 

submitting a pre-submission to discuss your regulatory plan, so that we may 

provide feedback and provide clarity on the least burdensome path and 

recommendations to bring your device to market. 

I will now turn the presentation over to Dr. Pena, for some closing remarks. 

Dr. Carlos Pena: Thanks Mike. So a few closing remarks, as we look at information about our 

division and industry and consumer education, to obtain more information. 

As Mike mentioned, the best way to engage going forward, about HDEs if 

interested, are via the pre-submission pathway. Not only do they allow for a 

free opportunity to engage our staff, but sponsors and developers can help 

exact investments help make business decisions and they can help enable 

realistic expectations about next steps in moving real product to the 

marketplace. 

Two, there are a variety of ways to learn about FDA and HDEs, from recent 

articles we have published to our neurological devices Web site online, to 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 24

today’s webinar on HDEs as well as prior webinars on the investigation 

device exemption, clinical studies phase of development, PMAs and the de 

novo regulatory pathway. And last, find out more about FDA. If you think 

it’s too early to contact us, that is exactly the right time to contact us, whether 

it be about the non-clinical work needed to move to clinical studies, the right 

clinical studies, to gather data about your device for an HDE, or the 

requirements to move your products to marketplace. 

The more communication we have, the better you are moving products to 

patients and caregivers, and I think you’ll be pleasantly surprised about the 

engagement with FDA. With that, I would like to turn it back to Irene, for a 

Q&A session. 

Irene Aihie: Operator, we’ll now take questions. 

Coordinator: Thank you. We’ll begin the question and answer session. If you would like 

to ask a question, or make a comment from the phones, please press star 1, 

make sure your phone is unmuted and record your name to introduce your 

question. To withdraw that request, you may press star 2. Once again, for a 

question or a comment from the phones, please press star 1 and record your 

name at this time. One moment while we standby for questions or comments. 

Dr. Carlos Pena: So while we’re waiting, this is Carlos. You know, one question that might 

have - or a couple of questions actually that we get, is often sponsors will ask 

us what type - specifically what type of non-clinical information is needed to 

get an HDE approved. Or exactly how many patients do I need to start the 

study? Or how many patients do I need to get an HDE approved. And to all 

those questions requires a little bit deeper dive into your device, the patient or 

population you’re studying, the indications for use, the study design as 

appropriate, as well as other technical questions that would all be best 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 25

addressed in a pre-submission. So again, you know, these types of detailed 

questions, it’d be great to have an open dialog with the agency via the presubmission process which is a free process to all. 

Coordinator: And we do have a question from the phones. Are you ready for that at this 

time? 

Dr. Carlos Pena: Yes. 

Irene Aihie: Yes. 

Coordinator: Thank you. Our first question or comment from the phones is from (Tom 

Oxley). Your line is open. 

(Tom Oxley): Hello everyone. Thank you very much for the webinar. It was very 

informative. I’m going to be cheeky enough to ask three questions. Do you 

want me to ask them all at once or should we do one at a time? 

Irene Aihie: One at a time would be helpful. 

(Tom Oxley): Okay. So the first one is given the limitations on the intended use for an HDE 

and given that you’re saying that the data from the HDE supported trial can be 

used into a future PMA submission, what is the impact of the expanded 

indication or the potential expanded indication into a PMA on the use of that 

data or the PMA, given that I guess my question is would you consider the 

inclusion of clinical data from the HDE, into the submission of the PMA, as a 

consideration of the total number of patients required in this study? 

Dr. Carlos Pena: So I can start off and if there are other - we have a lot of folks around the 

table. You could definitely use the clinical data as part of your submission. 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 26

Again, it would depend upon what type of data you’ve collected and how it 

will be applied to the expanded use. But definitely, that would be something 

we would look at closely. 

Josh Nipper: This is Josh Nipper. I’m the Director of PMA and HDE programs in the 

Office of Device Evaluation. And just to add onto what DR. Pena said, you 

know, a PMA can certainly cross reference the existing HDE data. You 

know, good clinical trial design issues are going to apply with respect to 

potential data pooling and whether or not, you know, the same patient 

populations were studied and things like that. But the data from an HDE can 

certainly be leveraged both preclinical and clinical data. 

So if your goal is to move from an HDE to a PMA and you’ve already done a 

lot of the bench testings, you know, that data does not need to be recollected 

or redone. You can certainly reference the old data. 

(Tom Oxley): Excellent. Thank you. My second question was I had heard that there had 

been changes on the definition of restriction of profit and annual reporting 

from the 21st Century CURES Act. But I got the impression from your 

presentation that that’s not the case. 

Josh Nipper: Again, this is Josh Nipper - 21st Century CURES did not change the profit 

eligibilities with respect to HDEs, that I’m aware of. And I’ve been pretty 

involved with the implementation of that, so I think that’s been consistent. 

(Tom Oxley): Thank you. And my last question was what is the best - what do you guys 

consider the best resource for the delving into and determining 

epidemiological populations for HDE applications? Do we just use peer 

reviewed journals that have looked at epidemiological data? Or are there 

particular references that you would prefer to see? 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 27

Dr. Carlos Pena: That’s a good question. I think, you know, it really depends upon - I don’t 

think we have a preference for one or another. It really depends upon what 

your device is and how does your device intend to be used and putting your 

package together and especially having that pre-submission beforehand, 

where you - we would help share with you how to present and put your 

package together for an HDE submission. 

(Tom Oxley): Thank you. 

Coordinator: Thank you. And again, as a reminder, for questions or comments from the 

phones, it is star 1. Make sure your phone is unmuted and record your name 

to introduce your question. To withdraw that request, you may press star 2. 

Once again, for questions or comments from the phones, please press star 1 at 

this time. One moment, while we standby for questions or comments. And 

again, that’s star 1 and record your name for a question or a comment. One 

moment please. Thank you. And our next question comes from (Brandon 

Shepherd). Your line is open. 

(Brandon Shepherd): Hi. This is probably a straightforward one, but I was just curious as to 

why the criteria changed from 4000 to 8000 with respect to HDE 

designations. 

Josh Nipper: Well the criteria - this is Josh Nipper again. The criteria was changed by 

Congress at the passing of 21st Century CURES a little over a year ago. You 

know, I think the intent is to get, you know, safe and effective medical devices 

out to the public. And the 4000 limit was fairly restrictive. It’s a very small 

patient population. And so I think the idea was to, you know, allow for 

slightly expanded access. I mean examples include things like cerebral palsy, 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 28

where the patient population was over 4000, but could probably fit within a 

broader scope. 

So I think it was essentially just an expansion of the program to hopefully 

reach additional patients. 

Irene Aihie: We’ll take our next question. 

Coordinator: Thank you. Our next question or comment comes from (Ming Chen Chu). 

Your line is open. 

(Ming Chen Chu):Hi. We just had a quick question about the approval timeline. We noticed 

that the modular HDE application had a 90 day review versus the normal 75. 

Why is that? And what’s the advantage of doing a modular over the original 

then? 

John Nipper: Again, this is Josh. A modular allows the review division to begin looking at 

some of the preclinical and technical information that may be finished prior to 

completion of your clinical data. So once the final module which is almost 

always a clinical module, is submitted, it is converted into a traditional HDE 

and has a 75 day clock. The benefit to going the modular route is the division 

may have already reviewed things like biocompatibility or software 

information and may have already given feedback for those pieces. And so 

therefore, may have less questions when it comes to looking at the HDE when 

it’s first reviewed. 

So once the clinical is submitted it may be a more straightforward process and 

you may have kind of a cleaner look at only the clinical information, as 

opposed to mixing a bunch of different preclinical or other even 

manufacturing issues. 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 29

(Ming Chen Chu):Okay. So the 90 day starts when the first module is submitted? 

Josh Nipper: So it’s 90 days for each module that you would submit. And companies can 

pick sometimes modules are two or three and sometimes, you know, they’re 

five or six depending on kind of how long it takes you to develop your device 

and how many - how much you want to break it apart. But the 90 day clock is 

for the individual modules. But once the clinical data is submitted, it would 

convert to an original HDE with a 75 day clock. 

(Ming Chen Chu):Okay. Thank you. 

Coordinator: Thank you. And again, as a reminder, it is star 1 and record your name for a 

question or comment, and star 2 to withdraw that request. Our next question 

or comment comes from (Carol McPherson). Your line is open. 

(Carol McPherson): Hi. I have two questions. And the first one you may have already 

addressed; I apologize if you did. The change from 4000 patients to 8000 - so 

the FAQ for HDE holders and IRBs and clinical investigators, etc. the 2010 

document is still the currently approve document. Correct? 

Josh Nipper: That is correct, although the 4000 to 8000 is a guidance document and it’s 

non-legally binding. The 4000 to 8000 was implemented immediately under 

the passing of 21st Century CURES. So we are - we have changed the 

operation, excuse me, of that, to 8000. 

(Carol McPherson): Okay. Great. And then my next question is for clinical sites that use the 

IRB approved HUDs, HDEs, does the FDA ever audit clinical sites? 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 30

Matthew Krueger:This is Matthew Krueger. I’m with the Office of Compliance, but I admit that 

I’m not actually in the bioresearch monitoring division. So I mean I think, 

you know, generally my understanding of bioresearch monitoring is they do 

audit clinical investigators. They do audit sites and IRBs that are responsible 

for, you know, maintaining the integrity of clinical studies or those kinds of 

patient protections. And that’s really what they’re geared towards is patient 

protection measures and that’s really the function of the IRB. 

So they do audit them. You know, I couldn’t speak at this time to, you know, 

what kind of frequency they do that on a routine basis, but I know that if there 

is for some reason, a for cause basis or they believe that there is, you know, or 

there is an allegation of some kind of malfeasance or something, the agency 

does have the authority and can inspect as required or as needed. You know, 

we obviously do, as a part of our preapproval review process, we do also in 

applications that have clinical data, we frequently do. 

Although it may or may not be utilized in every application. Exercise a role to 

perform oversight and just insure that the data submitted to the agency, you 

know, meets good clinical practice requirement and so we do exercise that as 

well. Hopefully that answers your question. I think if you have more specific 

questions, that really would be something I would encourage you to submit to 

the email address that’s on the last slide, so we can give you more specific 

information. 

(Carol McPherson): Great. Thank you so much. 

Coordinator: Thank you. And again, as a reminder, for any further questions at this time 

from the phones, please press star 1, make sure your phone is unmuted and 

record your name. And to withdraw that request, it is star 2. Once again, for 

final questions or comments, please press star 1 at this time. One moment 
FDA Webinar

Moderator: Irene Aihie

12-18-17/12:00 pm

Page 31

while we standby for any questions or comments. And I am currently 

showing no further questions or comments. I’d like to turn it back over to our 

speakers for any closing remarks. 

Irene Aihie: Thank you. This is Irene Aihie. We appreciate 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 Thursday, January 4th. 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 the webinar, please 

complete a short, 13 question survey, about your FDA CDRH webinar 

experience. The survey can be found at www.FDA.gov/CDRHWebinar, 

immediately following the conclusion of today’s live webinar. 

Again, thank you for participating and this concludes today’s webinar. 

Coordinator: Thank you. That does conclude today’s conference call. Thank you for your 

participation. You may disconnect at this time. 

END