FDA HDE Webinar 

Moderator: Irene Aihie

10-21-19/12:00 pm ET

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FDA Webinar: Humanitarian Device Exemption Program

Moderator: Irene Aihie

October 21, 2019

12:00 pm ET

Coordinator: Welcome and thank you for standing by. At this time, all participants are in a 

listen-only mode until the question and answer session. 

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

disconnect at this time.

I will now introduce your conference host, Ms. Irene Aihie. 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. On September 6, 2019, the FDA 

issued a Final Guidance on the Humanitarian Device Exemption Program. 

This guidance provides clarity to industry and FDA staff about the current 

review practices for the Humanitarian Device Exemption Program. This 

programmatic guidance addresses commonly asked questions about HDEs and 

Humanitarian Use Devices, including FDA actions on HDE applications, 

post-approval requirements, and special considerations for devices marketed 

under the HDE Program. 
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Today, Stephanie Sheddd, Biomedical Engineer, in the Office of Product 

Evaluation and Quality here in CDRH, will present an overview of the 

guidance document. Following the presentation, we will open the line for 

your questions related to information provided during the presentation. 

Additionally, there are other Center subject matter experts here with us today 

to assist with the Q&A portion of our webinar. 

Now, I give you Stephanie...

Stephanie Shedd: Thank you, Irene. Hello, my name is Stephanie Shedd. I am a biomedical 

engineer in OHT6, the Office of Orthopedic Devices. I’m here today to 

discuss the recently issued guidance on the Humanitarian Device Exemption 

or HDE program which I worked on while I was on temporary assignment as 

a policy analyst to the Division of Submission Support in the Office of 

Regulatory Programs in the Office of Product Evaluation and Quality in 

CDRH.

Today's agenda includes definitions and objections relevant to today's 

webinar, a brief background of the HDE program, the scope of the recently 

published guidance document, the expected content, review steps, and 

timeline of an HDE application, post-approval requirements for an approved 

HDE, special considerations for HUD use under HDE, a summary of 

significant changes in the HDE guidance compared to the last version, and 

finally resources that are available to you. We will end the webinar today with 

time for questions from the audience.

I'd like to define the following terms before getting further into this talk. 

humanitarian use device or HUD is medical device that is intended to benefit 

patients in the treatment or diagnosis of diseases or conditions that affect or 

are manifested in not more than 8000 individuals in the US per year. A 
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Humanitarian Device Exemption or HDE is the marketing application for a 

HUD. These applications are exempt from the effectiveness requirement of 

the Safe Medical Devices Act and are subject to certain profit and use 

restrictions as we'll go over later in this talk.

An Institutional Review Board or IRB is responsible for, among other things, 

the oversight of the use of HUDs at medical facilities per the FDA regulations 

that govern IRBs. An appropriate local committee is defined in the guidance 

as a standing committee at a medical facility that has expertise and experience 

in reviewing and making treatment decisions for clinical care especially in the 

area of rare diseases.

Our objectives for this webinar today are to provide an overview of the scope 

of the HDE program as described in the guidance document which was issued

on September 6th and to review significant changes in the most recent 

guidance document which supersedes the prior version that was issued back in 

July 2010. 

The HDE program has evolved over time and encourage the development of 

devices designed to treat or diagnose rare conditions. In 1990, the Safe 

Medical Devices Act included a provision to exempt qualifying devices from 

the requirement to demonstrate a reasonable assurance of effectiveness per 

Section 514 and 515 of the Food, Drug and Cosmetic Act. 

In 1997, the FDA Modernization Act allowed for the use of HUDs approved 

under an HDE at medical facilities without prior IRB approval in certain 

emergency situations. In 2007, the FDA Amendments Act allowed HUDs

indicated for use in pediatric patients or in a pediatric subpopulation to be sold 

for profit. In 2012, the FDA Safety and Innovation Act, or FDASIA, further 
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expanded the eligibility of devices approved under HDE that are able to make 

a profit.

What brings us here today is the 21st Century Cures Act or simply Cures Act 

which became effective in December of 2016 and specifically calls for 

modifications to the HDE program. Of note, the Cures Act modifies the HUD 

threshold to not more than 8,000 individuals in the United States per year 

which is an increase in the previous threshold of 4,000 individuals. In 

addition, the requirements that IRBs need to approve the use of HUDs at 

medical facilities was revised to also include appropriate local committees. 

And we will discuss what that means later on in the talk.

There is a specific commitment related to the HDE program in which FDA 

committed to publish a draft guidance within 18 months which defines the 

criteria for establishing probable benefit in an HDE application. This draft was 

published in June of 2018. The current guidance represents the finalization of 

that draft guidance which incorporates responses to public comments that 

were received.

The scope of the guidance document encompasses most stages of the HDE 

review including operational aspects such as filing and substantive review,

and potential decisions that can be made on an HDE application. The 

guidance document discusses the principal criteria that FDA uses to determine 

probable benefit and also how FDA will make the assessment of whether 

probable benefit of the HUD outweighs the risk of injury or illness from its 

use. In addition, post-approval requirements and special considerations

specific to the HDEs are discussed. Finally, decision tools for FDA staff or for 

reviewing HDE applications are introduced.
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For a complete HDE application to be submitted to FDA, it is important to 

note that the HUD designation should be submitted to and approved by our 

Office of Orphan Products prior to the HDE submission. This is a review 

from the Office of Orphan Products that agrees that the patient population is 

less than the threshold of 8,000 patients per year. Please see the guidance 

document which has also been revised recently for important considerations

when applying for a HUD designation.

The filing review for an HDE application assesses the content of the 

submission and determines whether it is administratively complete. A filing 

checklist for use by industry and FDA reviewers is provided in Appendix A of 

the guidance. The applicant is expected to provide the information requested 

or provide a justification for any alternative approaches used for any of these 

items. The filing decision is to be made within 30 days from the date the 

HDE was received. 

Reviewers are strongly encouraged to use interactive review to obtain any 

missing information either during the filing or substantive review. Thus it is a 

best practice for applicants to be prepared to respond to FDA requests in a 

timely fashion. A reviewer would expect that the following major categories 

and information would be provided in an administratively complete 

application. The device description that includes all components and 

accessories and their mode of action. Design drawings and specifications and 

materials including a citation of any applicable material standards.

The indication for use statement as proposed in the HDE should be consistent 

with the HUD-designated disease or condition and any changes to this 

language should be justified. 
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The HDE should contain valid scientific evidence that demonstrates the safety 

and probable benefit of the device. This information may include bench, 

animal and/or clinical data. Note that we support the principles of the three 

Rs, to reduce, refine and replace animal use in testing when feasible. We 

encourage applicants to consult with us if they wish to use a non-animal 

testing method and we will consider if such an alternative method could be 

assessed for equivalency to an animal test method. 

The guidance also encourages the collection of patient preference information 

that may contribute to the determination of safety and probably benefit. The 

application should provide a discussion of why, based on the data provided, 

the probable benefit outweighs the risk of use of the device. The application 

should also include manufacturing information in accordance with the quality 

system regulation as well as labeling including physician and patient labeling 

if applicable. Note that patient labeling is often applicable especially in the 

pediatric patient applications. 

I want to point out some elements that are unique to the filing of an HDE. As 

stated earlier, the HUD designation should already be obtained prior to 

submission of the HDE and a copy of or reference to the HUD designation 

letter should be provided. The amount to be charged for the device should be 

provided. This information should be provided regardless of device's 

eligibility for profit-making. If this amount exceeds $250 , then a report must 

be provided verifying that the amount charged does not exceed the cost of the 

device's research, development, fabrication and distribution.

Information regarding comparable devices should also be provided. The 

applicant should conduct a search within the device space and provide a 

statement that no other comparable device other than a HUD approved under 

HDE or a HUD for use under an approved clinical investigation is available to 
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treat or diagnose the disease or condition. If the statement cannot be provided 

and there are alternative devices available, then HDE may not be an 

appropriate marketing pathway.

Once an application has been determined to be administratively complete via

the filing review, a review of the safety of probable benefit of the device 

occurs during the substantive review phase. In order to demonstrate safety, 

the HDE application must demonstrate the device will not expose patients to 

an unreasonable or significant risk of illness or injury and the probable benefit 

to health from use of the device outweighs the risk of injury or illness from its 

use. Which takes into account the risks and probable benefits of currently 

available devices or alternative forms of treatment.

Unique to HDE review is the standard of probable benefit as HDEs are 

exempt from the requirement to demonstrate effectiveness which is necessary 

for other marketing applications such as PMA premarket approval. As 

defined in the guidance, probable benefit can be determined when there's 

evidence for FDA to reasonably conclude that patients are likely to benefit 

from the use of the device. This could take into account many factors 

including the type of benefit, the magnitude of the benefit, the probability of 

the patient to experience one or more of those benefits, the duration of the 

effects, patient perspectives, and/or a care partner such as parent or aide

perspective. Many of the HDE applications are for pediatric patients,

pediatric subpopulations, thus, the care partner or a parent or aide perspective 

are often important in the decision-making. 

The reviewer's determination of whether the HDE demonstrates probable 

benefit includes many considerations. The reviewer may accept a greater level 

of uncertainty in the data as a reasonable assurance of effectiveness is not 

required. The reviewer may consider the intended use of the device including 
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the target patient population and the size of the population. For example, the 

smaller the patient population, the greater the uncertainty FDA would expect. 

The reviewer may take into account currently available alternative treatments

or diagnostics and may take into account patient perspectives on risk, 

uncertainty and probable benefit. 

In a parallel effort, there has been a lot of work on defining uncertainty in 

benefit-risk determinations which recently ended in a final guidance document 

which further describes the use of uncertainty in decision-making. We highly 

recommend you consult this guidance as these principles apply for HDE 

review as well. 

Upon completion of the substantive review, an FDA action is to be made 

within 75 days of the receipt of the submission. The guidance discusses the 

following major actions; approval order, approvable order, major deficiency 

letter, not approvable letter, or denial order. Major amendments including 

responses to a request for additional information letter will extend review time 

up to 75 additional days. In addition, a submission is considered voluntarily 

withdrawn if there is a failure to respond to any request for additional 

information such as a filing or major deficiency letter within 75 days unless an 

extension is granted. An extension may be granted to respond up to 360 days 

from the date of the additional information request. 

Once an HDE is approved, it is subject to several requirements unique to 

HDEs. An IRB must provide oversight at medical facilities where HUDs are 

used. The statutory language now allows either an IRB or an appropriate 

local committee or ALC to review and approve the use of a HUD to treat or 

diagnose patients at that facility. An appropriate local committee may include 

a standing committee at the facility that includes physicians with experience 
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and the treatment of rare diseases or conditions, as we'll discuss further in the 

next slide.

It's important to note here that approval for individual HUD use is not 

required. A generalized approval may be granted for this facility. Also the 

use of an ALC does not change the provision that for certain emergency uses 

prior approval by an IRB or appropriate local committee is not required. 

An appropriate local committee is defined in the guidance as a standing 

committee for the facility that has expertise and experience in reviewing and 

making treatment decisions for clinical care, particularly in applying 

innovative medical device technologies to clinical care.

The committee may include physicians with experience and treatment of rare 

diseases or conditions. Examples of these types of committees which may 

already exist within a facility include a peer review committee, credentialing 

committee or quality care committee. 

The guidance also provides recommendations for IRB or ALC review of an 

application for HUD use at their facility. FDA recommends the review of the 

following information at a convened meeting of the committee; a copy of the 

HDE approval order, a description of the device, the product labeling, the 

patient information packet that may accompany the HUD, a sample consent 

form for the use of the HUD in clinical care if required by the IRB or ALC or 

by the facility policy. A summary of how the physician proposes to use the 

device include a description of any screening procedures, the HUD procedure 

and any patient follow-up visits, tests, or procedures. Not everything on this 

list may apply in all circumstances, but it is to be used as guideline.
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Additional post-approval requirements unique to HDE include reporting of 

adverse events. All adverse events associated with use of the HUD whether 

expected or not, must be reported and evaluated in accordance with the 

medical device reporting requirements in 21 CFR Part 803. Specifically 

device manufacturers and user facilities should report - should submit reports 

to FDA and the IRB or appropriate local committee that approves the use of 

the HUD. In addition, adverse events that occur in HUD that are approved 

and labeled for pediatric patients or a pediatric subpopulation and are also 

exempt from the profit prohibition are reviewed periodically by the FDA's 

pediatric advisory committee or PAC.

Additional requirements unique to approved HDEs include the submission of 

HDE supplements to modify the approved device. Supplements generally 

follow the review guidelines for PMA with some changes to the review 

timeline. However, it is important to note that any request for new 

indications should be accompanied by a new HUD designation through the 

Office of Orphan Products. 

Periodic reports, which are often annual reports, are specified in the approval 

order and are to be submitted post-approval. For HDEs these reports should 

include updated information to demonstrate that the HUD designation is still 

valid, and the patient population has not changed. In addition an updated 

discussion of comparable devices should be provided and an explanation of 

why the device would otherwise not be available without the HDE approval,

to make sure the HDE approval is still valid. 

Similar to a PMA approval, a post-approval study may be required as a 

condition of approval to understand long term performance or evaluate the 

learning curve or training issues associated with the use of the device. A full 

protocol or a protocol outline including the relevant enrollment, follow-up and 
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reporting timepoints is agreed upon prior to HDE approval. If only a protocol 

outline is agreed upon at time of approval, a full protocol may be developed 

following approval in a protocol supplement to the HDE. 

Recommendations for developing and conducting post-approval studies are 

outlined in the guidance document “Procedures for handling post-approval

studies imposed by PMA order.” While this document is specific to PMA, 

much of the processes are similar for HDE post-approval studies. 

Next we will discuss special considerations for HDE holders when marketing 

their device. First we will discuss profitability. HUDs under an HDE cannot 

be sold for an amount that exceeds the cost of research and development, 

fabrication and distribution of the device, in other words for profit, unless the 

patient population fits the following unique circumstances. The device is 

intended and labeled only for pediatric patients or in a pediatric 

subpopulation. The disease does not occur in any pediatric population or 

pediatric sub-groups. For example this could be a population susceptible to 

age-based disease such as Alzheimer's, which is not a HUD qualifying 

condition, but is used here as an example. Or the disease or condition occurs 

in pediatric patients in such numbers that the development of the device for 

such patients is impossible, highly impracticable, or unsafe.

The definitions and examples illustrating the terms in possible, highly 

impracticable and unsafe are provided in the guidance. For example 

geographic dispersion of patients and/or sites would likely not be considered 

impossible or highly impracticable because of the speed and efficiency of 

modern communication tools and would not be considered an extraordinary 

circumstance. The applicant should provide adequate supporting 

documentation in the HDE to support the request for exemption from the 

profit prohibition. 
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A special consideration for HDE holders includes the annual distribution 

number or ADN. If eligible, the HUD can be sold for profit up until the 

number of devices sold excess the ADN. If the HDE application or 

supplement, I’m sorry. In the HDE application or supplement, the applicant 

should provide the number of devices per year that are reasonably needed in 

order to treat the conditions in each individual and provide adequate 

documentation to support such number. The ADM will be greater to, I’m 

sorry. The ADM will be equal to or greater than 8,000 depending on how 

many devices per year are reasonably needed to treat, diagnose or cure an 

individual. 

For example, if two devices are needed, then the ADN is 16,000 and the HDE 

holder can sell up to 16,000 devices for profit per year. Once the ADN has 

been exceeded, then the sales for the HUD for the remainder of the year are 

subject to the general prohibition on profit. Unless the FDA approves an 

ADN modification request in an HDE supplement. 

A special consideration for HDE holders includes the information that's 

provided to patients and in the labeling. FDA does not require informed 

consent from the patient that is being treated or diagnosed with an HDE 

approved HUD as it is considered an approved device. However, the IRB or 

ALC may choose to require additional information be provided to patients or 

informed consent to be obtained. Should written documents be provided to 

patients, much of the information that was approved under the HDE and the 

patient labeling should be included. 

In addition, all labeling documents should be truthful and non-misleading. As 

required in the regulation, the labeling should include the statement that this is 

a humanitarian device, authorized by federal law, for use in treatment or 
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diagnosis of a disease or condition and that the effectiveness of this use has 

not been demonstrated. 

A special consideration for HDE holders includes those for pediatric use. 

Pediatric is defined by the FD&C Act as patients who are 21 years or younger 

that means up to but not including their 22nd birthday at the time of, sorry, at 

the time of diagnosis or treatment. As discussed previously, HUD labeled for 

use in pediatric patients or in a pediatric subpopulation may be eligible to be 

sold for profit. 

An HDE application may be intended for use in both pediatric and adult 

populations. In that case, an application should include data supporting the use 

in both pediatric and adult populations. Or an appropriate rationale that 

addresses how the data provided for one population are sufficient to support 

approval of an HDE application with indications for use in both populations. 

For example, how an adult dataset supports both adult and pediatric use.

Additionally, HUDs approved via HDE for pediatric populations are required 

to be reviewed annually by the pediatric advisory committee or PAC. This 

committee advises the FDA commissioner on emerging issues in pediatric 

research and reported adverse events, or other information of interest.

This review ensures that the HDE remains appropriate for the pediatric 

populations for which it was approved. The PAC also conducts periodic 

review of adverse events for HUDs when they are exempt from the profit 

prohibition. Additional information on PAC membership tasks and upcoming 

meetings are available on FDA's website at the link shown here and their last 

meeting was in April of 2019. 
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So finally, transitioning over to the HDE reviewer tool. The guidance 

provides several tools for use by FDA reviewers during the review of an HDE 

application. Of note, the filing checklist is incorporated into the guidance and 

is provided in Appendix A. The checklist format helps to ensure that the 

application contains the necessary information to conduct a substantive 

review. The elements on the checklist stem from either statutory or regulatory 

requirements and the checklist also includes some elements that alone would 

not be the basis for a refuse to file but FDA strongly recommends providing in 

order to facilitate substantive review and avoid significant delay of review of 

the submission. For example, providing sections that are key articles in 

English. Generally the format and content of the filing checklist are 

consistent with the analogous checklist for other types of premarket 

submission. For example, the PMA RTA checklist. 

Concerns identified by the agency regarding results and outcomes of 

nonclinical and clinical studies to should be addressed in the substantive

review and should not preclude a filing decision. In other words, the FDA 

should not refuse to file an HDE application because we have reviewed the 

data and believe that the application is ultimately inadequate to meet the 

standard for HDE approval. This should be addressed in the substantive 

review. 

Additional tools provided in the guidance include Considerations for the 

Probable Benefit-Risk Assessment in Appendix B and Probable Benefit-Risk 

Assessment Summary in Appendix C. These worksheets provide flexibility 

and use of scientific judgment in assessing totality of evidence to determine if 

a specific device meets the standard for HDE approval. 

They were designed to allow FDA to take into account considerations relevant 

to HDE applications, for example a relatively small patient population, under 
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a framework that is consistent across device marketing submissions, for 

example, a PMA. These worksheets prompt reviewers to consider specific 

criteria for probable benefit, risk, and sources of uncertainty when evaluating 

the data provided.

So in summary, the guidance provides several updates to the HDE process in 

order to facilitate innovation and development of devices for rare diseases and 

conditions. Per the Cures Act a HUD is now defined as a device for use in a 

patient population that does not exceed 8,000 patients per year. This is a 

larger threshold compared to the previous 4,000 patients per year.

The final guidance provides definitions and criteria for determining probable 

benefit and assessing whether the probable benefit outweighs the risk of use in 

a more consistent and more predictable manner. The guidance allows more 

flexibility in use of appropriate local committees in addition to the IRBs to 

approve HUD use at medical facilities. And the guidance provides reviewer 

tools to ensure consistency as well as flexibility in reviewer decision-making.

So this is a busy slide, but we wanted to make you aware of a small sample of 

the resources that are appropriate to use when developing an HDE application. 

As discussed earlier, PMA- related resources may be beneficial in certain 

situations. In addition, several concepts such as benefit risk and uncertainty 

were developed in parallel with this guidance and were incorporated into this 

HDE guidance and review process.

So this concludes our presentation and we're now available for any questions 

from the audience.

Coordinator: We will now begin our formal question and answer session. If you have a 

question, please press Star 1 on your touchtone phone. Only record your first 
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and last name. To withdraw your question, you may press Star 2. So once 

again, to ask a question, please press Star 1 on your touchtone phone. One 

moment for the first question.

Stephanie Shedd: Okay, so while the operator is queuing up some questions, I wanted to 

introduce my co-presenter. I'm here with Josh Nipper. He's the Director of the 

Division of Submission Support within OPEC. 

Josh Nipper: Thank you.

Stephanie Shedd: And one of the most frequently asked questions that we get, the question, isn't 

it burdensome for IRBs to have to approve each use of a HUD at their 

facility? And the answer is that the IRBs or the ALCs do not have to approve 

each individual use. They may provide a blanket approval for any patient 

that's deemed appropriate for treatment with that HUD at their facility.

Do we have any questions? Another frequently asked question that we get. 

How many HDEs are approved each year? So we generally approve two to 

five HDE applications per year. And we have approved about 76 since the 

program was started in 1990. The FDA website keeps a list of recently

approved HDEs for you to take a look at.

Woman: We'll take our first question.

Coordinator: The first question is coming from (Kim Jaffrey). You may ask your question.

(Kim Jaffrey): Hi there. I was wondering. Would the FDA allow a device under the HUD to 

be used with an unapproved but clinically tested therapy? Or if the device 

needs to be used with an already approved therapy? 
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Josh Nipper: So when you say therapy are you referring to like a pharmaceutical or a drug? 

If so, I would say, you know, in order to be approved under the HDE 

application, everything would need to be approved or on label. We do have 

HDEs that are used with a drug or a biologic. But those drugs or biologics are 

legally marketed therapies. So I'm not sure if that was your question or not.

Coordinator: Once again, if you do have a question, please press Star 1 on your touchtone 

phone. The next question is coming from Mr. (McDonald). Your line is open.

Mr. (McDonald): Thank you. I had the question about the language regarding IRBs and ALCs. 

And the question is, in a facility not affiliated with an institution, and so they 

have no established IRB, but they do have a standing ALC, how would IRB 

oversight be completed and documented?

Stephanie Shedd: You know, you're right. There is a distinction between IRB oversight at a 

facility versus use of the HDE approved device in certain cases. So yes, the 

facility needs to have that IRB oversight and then the IRB or an appropriate 

local committee can review the individual cases for the HDE use. 

Josh Nipper: Yes, I would agree. Every - to use at a facility, the facility must have IRB 

oversight according to the statute. That's not to say that the IRB has to review 

the use of that. It could be an appropriate local committee, but there does have 

to an IRB in place at the facility. It can be a sort of a national or central IRB. 

So there, you know, we're aware that there are national level IRBs that 

approve or that oversee facilities across the country. And that's perfectly fine. 

It doesn't have to be a local, you know, in-house IRB, but there does need to 

be IRB oversight.

((Crosstalk))
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Coordinator: Once again, if you do have a question, please press Star 1 on your touchtone 

phone. The next question is coming from (Kathy Moore). Your line is open.

(Kathy Moore): Hi there. So if we understand correctly from the slides, ALC can review the 

HUD alternatively from an IRB. Is that correct?

Stephanie Shedd: Yes, that's correct.

(Kathy Moore): How should the - how should we verify that the ALC is constituted 

appropriately? I think for IRBs we need to be looking for IRB roster or an 

FWA assurance statement? If I understand correctly, you're not requiring an 

IRB to review it. It can be an ALC. So how do we ensure that ALC is 

appropriately constituted?

Josh Nipper: So that's a great question and not one that is clearly spelled out in the Act or 

even in our guidance. You know, my best advice is that manufacturers and 

HDE holders ask those questions. And so if a facility is using an appropriate

local committee, I believe the manufacturer should verify that it - they believe 

it's appropriate. There - when those provisions were put into the Act, there 

wasn't a lot of clear direction as to what constituted an ALC. FDA has 

attempted to provide some examples of that. And we're fairly clear that those 

examples should include people either familiar with the clinical specialty or 

with a rare disease type patient population. 

But we don't provide, you know, clear stipulations. You know, as I'm sure 

aware, IRB rosters and procedures are more spelled out in the regulations and 

this ALC language was somewhat new to us as well. We honestly think they 

should be operated fairly close to that of an IRB, but there could be some 

differences that we're aware of. 
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Coordinator: One again if you do have a question, please press Star 1 on your touchtone 

phone. The next question is coming from (Pata). Your line is open.

(Pata): Hi there. Once clinical data is obtained post HDE for a HUD device, then at 

some point can those be converted to a PMA for standard indication based on 

patient data obtained during this forced HDE process?

Stephanie Shedd: Yes, that is a potential pathway. It's most likely that once an HDE is 

approved, it goes on to collect additional data which is then used to meet the 

standard for a PMA approval which is safety and effectiveness. So most 

likely that includes additional or broader dataset to support that effectiveness 

definition.

(Pata): So but we can just take that data then and assuming we have enough data to 

support this new broad indication and by sort of PMA based on the data then?

Josh Nipper: Yes, I mean there have been multiple instances in the past where a sponsor of 

an HDE continues to collect data either through a post-approval study or on 

their own behest. And collects additional data and gets to the point where they 

believe they can prove effectiveness as opposed to probable benefit. And they 

come in and there have been 5 or 10 examples where we've had an HDE that 

went onto get PMA.

(Pata): Thank you.

Coordinator: The next question is coming from (Allison Komiyama). Your line is open.

(Allison Komiyama): Hi, thank you so much for this presentation. Actually the last caller, you 

answered my question within your response. I was going to ask how many 

have gone onto have a successful PMA. And the answer is about 5 to 10. So 
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and you said there were about 70 or 80 that have been approved? Is that 

correct?

Stephanie Shedd: Yes, that's correct, about 76 since 1990.

(Allison Komiyama): Okay, thank you. Thanks to the last caller.

Coordinator: The next question is coming from (Sherry Shambley). Your line is open.

(Sherry Shambley): Hi, thank you for this webinar, very informative and quite timely. My 

question for you today is approximately how many patients would be 

recommended by the FDA in an HDE study?

Stephanie Shedd: I mean that's going to vary case-to-case. It's going to come down to the 

intended patient population for the device as well as that idea of uncertainty. 

How many patients will be determined by how much uncertainty will be 

acceptable within that application. You're going to have examples where you 

want less uncertainty. An example is where, you know, endpoint is mortality 

versus perhaps more uncertainty would be acceptable in an indication where 

the endpoint is pain.

So it's hard to dictate an exact number. It may not be statistically powered, I'll 

put it that way. But you're still going to need enough information to create 

that standard of probable benefit via valid scientific evidence.

Josh Nipper: I agree completely, and I would also say, you know, there is safety threshold 

as well. And there, you know, the probable benefit is kind of a key 

differential from other areas. But you do need to demonstrate some, more than

some, you do need to demonstrate safety of the device as well. And so often 

an HDE study will be, I don't want to use the word powered because that may 
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overstate it but centered around collecting enough safety information to prove 

that, you know, the device is safe for use.

You know, my best advice for companies exploiting the pathway is to come in 

with a pre-submission. Discuss with the FDA review team what their 

expectations may be for an HDE type study because as (Stephanie) said, it's 

incredibly variable. I've seen very small studies for patient populations that 

are very small. Then I've seen them where they are almost PMA like for some 

of the HDE populations that kind of get up close to that threshold. 

So that's a very difficult question to answer and I guess our answer is it 

depends.

(Sherry Shambley): Thank you.

Coordinator: Once again, if you do have a question, please press Star 1 on your touchtone 

phone. The next question is coming from (Erika). Your line is open.

(Erika): Hi. This is (Erika) and from the IRB perspective we were, I think, all very 

excited to find that we could give this duty to another committee. However, 

you've explained that IRBs remain responsible for oversight which sounds to 

me like we now have two committees instead of one doing something that we 

really don't understand fully. So could you explain what the difference is 

between the appropriate local committee doing review and the IRB now doing 

oversight? What do you mean by those terms?

Josh Nipper: Great question, and as far as the oversight goes, the Act specifically states that 

a - to be - for an HDE to be used a facility, they must have IRB oversight. 

What the IRB decides to defer down to the appropriate local committee is 

really kind of up to them. So I would say that an IRB could review the, you 
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know, there was a question earlier about the, you know, the makeup or 

constitution of those appropriate local committees. That could be what the 

IRB looks at. They could say you want to make sure that that ALC has an 

appropriate makeup, but not necessarily review the merits of the HDE. They 

could, you know, they could both if they wanted to be very hands-on. Or they 

could just say, you know, the ALC language is somewhat confusing which we 

acknowledge. And, you know, continue to provide direct oversight of the 

HDE study.

You know, we've heard from some IRBs that's their intent. They don't want to, 

you know, defer this responsibility and that's perfectly within their right and 

purview.

Stephanie Shedd: Right, I mean the IRB oversight includes stuff that's applicable across the use 

of devices at the facility. So is there appropriate informed consent? Is there 

appropriate communication with the patient? And then can, as (Josh) said 

they can delegate down certain responsibilities and to the ALC such as 

reviewing the HDE approval and that specific material and whether use of that

device is applicable to the patient that's currently being reviewed. 

So it's additional flexibility within the facility that doesn't necessarily need to 

be used, if that makes sense.

Coordinator: The next question is coming from (Angelique Gupta). Your line is open.

(Angelique Gupta): Hi, thanks. My question is regarding the ADN or the annual distribution 

number. I was just wondering that you didn't get an ADN assigned on 

approval. And maybe not in subsequent annual reports and you don't have 

one. Under what circumstances would you be assigned an AND?
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Stephanie Shedd: You would be assigned an ADN. That would be part of the approval order at 

the time of HDE approval. And you can request an update to that ADN at any 

time via supplement to the HDE.

Josh Nipper: To be clear, the ADN is only required if you're requesting profit. So if you, 

you know, if you're an HDE which, to be clear, most are, if you're an HDE 

that occurs in adults and pediatrics and you don't have that pediatric data, 

then, you know, you're prohibited from making a profit. And the ADN rules 

essentially don't apply. If you are ...

(Angelique Gupta): Okay.

Josh Nipper: ... pediatric only or you've requested and provided enough documentation to 

demonstrate that you don't you know, that you fell within one of the other two 

criteria, then you'll be assigned an ADN at the time of either approval if you're 

requesting a profit when you submit, or you can submit a subsequent 

supplement and request to make a profit. And request an ADN and we will 

evaluate that and basically, you know, if we agree that you meet the criteria 

for earning a profit, we will put that in the letter and then assign an ADN at 

that time.

(Angelique Gupta): Okay, thank you.

Coordinator: And the next question is coming from (Mahe). Your line is open.

(May): Hello, this is actually (May). Hi. I was going to ask the same question that 

(Angelique) just asked. And but I just wanted to clarify that the profitability 

exemption is really only for pediatric applications. Is that correct?
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Stephanie Shedd: Most likely it's a pediatric application, but that's second criteria. It's for - the 

example is an age-related condition such as Alzheimer's with no chance for a 

pediatric patient to be included. But it's only that adult population. That also 

could be eligible for profit-making.

(May): So thank you for that.

Josh Nipper: (Unintelligible).

(May): Sorry, so sorry.

Josh Nipper: (Unintelligible), I'm sorry. Go ahead.

(May): No, I think you were about to just answer my question and that was if this 

particular disease did not occur in pediatrics and occurs in specific adult 

populations and occurs in a small part of the population and it has been 

eligible for an HDE, would it still be possible to be - to apply for an ADN 

even if there's very little application in pediatrics? (Unintelligible).

Josh Nipper: Well, so very little and none is different. 

(May): Pardon:

Josh Nipper: So, very little in pediatrics and none in pediatrics are different. 

: If you can - if a sponsor can prove that there is no pediatrics, you know, 

through established literature, if they can prove that it's just doesn't or can't 

occur in pediatrics, then they can earn a profit. If it's very small number in 

pediatrics, they either have to provide data to show that the HDE can be used 
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for that subset. Or provide a justification saying like it's basically impossible 

to study pediatrics because it's so small. 

We've approved that kind of final clarification a couple of times, but I can tell 

you we're fairly critical of that, you know, when sponsors try to justify that. I 

mean if it exists in the pediatric subpopulation, we are trying to get them to 

study in those populations. But I mean on your comment, I think very little 

and none are different categories within the Act.

(May): That is great to know. Thank you very much. I really appreciate that 

distinction. Thank you.

Coordinator: Once again, if you do have a question, please press Star 1 on your touchtone 

phone. The next questions is coming from (Sherry). Your line is open.

(Sherry): Hi, thank you again for the additional question. For the 5 to 10 HDEs which 

later become PMAs, did they require an amended or supplemented indication 

for use? I understand the difference just between the safety and the efficacy, 

but does it require a different indication for use between the two applications? 

Josh Nipper: I'm not 100% sure I understand your question. But in order to go from HDE to 

PMA, the sponsor would need to submit a full PMA. And that includes user 

fee. It includes, you know, submission of any additional data they've 

collected. They could choose to - it's really up to the sponsor. They could 

choose the identical indication of the HDE. They have additional data. They 

could extend that outward and say, you know, so if the HDE were for only, 

you know, making this up, but only Class 3 and 4 condition. And the PMA 

had data for Classes 1, 2, 3 and 4. The PMA could have that additional 

broader indication. It would really be up to the sponsor and depend on kind of 

the data they selected. 
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(Sherry): Thank you.

Coordinator: The next question is coming from (Judy). Your line is open.

(Judy): Yes, hi thank you. Could you speak to the reporting requirements for offlabel use such as reporting to sponsors and reporting to IRBs?

Stephanie Shedd: Yes, the guidance goes into a little bit. You know, we're not here to dictate 

practice in medicine. The surgeons can use the device as they see fit. If it 

does come to reach a threshold where that off-label use is going to require 

marketing application, then yes, the surgeons, the users of the device should

be reporting back to the sponsors. And the sponsors would then prepare the 

marketing application for that off-label use. That's one of the expectations. 

Josh Nipper: Yes, I mean to add on a little. It's up to the IRB would they approve their use 

for. Some IRBs have been very strict and only approve it for on-label. And 

then basically say off-label use is not allowed at their facility. That their -

that's the IRB's prerogative. They can do that. Others are fairly broad and say, 

you know, it's up to the physician to use it how they see fit. But physician is 

not inherently required to report that to their IRB or their sponsor or the 

manufacturer. You know, it's a best practice for them to summarize the use. 

To say, you know, here's how they, you know, at least to their IRB, here's how 

we're using the device and the results we've seen. But it's not, you know, we -

FDA does not regulate practice of medicine and so it's not inherently a 

requirement to report that to the IRB, to the company or to us for that matter.

(Judy): Thank you very much.

Coordinator: And the next question is coming from (Maria). Your line is open.
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(Maria): Hello, I'd like to understand, or can you comment if the pre-submission 

program, Q-Sub program is useful during the HDE process the same what that 

it's or similar way that it's used during the 510K process? Or well of course 

during the PMA process it's usually required. But I'm just not sure due to the 

process, the HDE process itself, whether a pre-sub is actually useful?

Stephanie Shedd: Yes, we strongly recommend use of the pre-sub process. That could come 

before or after the HUD designation. That's kind of an independent process 

through the Office of Orphan Products. But the pre-submission process 

through your OHT or your review office could be very helpful in determining 

what that HDE submission would look like. What sections would be 

included? How to present your data? And any other questions that come up 

from your review team before the HDE is submitted and that 75-day review 

clock starts. So if there's at all any questions about what your HDE should like 

and what should be included. We highly recommend the pre-submission

process.

(Maria): Thank you.

Stephanie Shedd: Yes.

Coordinator: Once again, if you do have a question, please press Star 1 on your touchtone 

phone. The next question is coming from (Caroline McPherson). Your line is 

open.

(Caroline McPherson): Hi, sorry. My question was already answered. It was about use of 

off-label use of HDEs, but I actually do have a question on that same line. 

When the HDE is used off-label and there's no IRB approval for use of the 
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device, but it's used in an emergency situation, can you speak to your thoughts 

on that?

Josh Nipper: In those instances, we do ask that, I think it's the regulations even that we do 

ask that there is - that they do report back to the IRB and the sponsor within 

five days post-emergency use. You know, obviously we're not going to want 

to discourage the use in an emergency if that's in the best interest of the 

patient. But, you know, if there is no IRB and (unintelligible) no IRB 

approval at that point, we do ask that they notify the IRB and the company 

within five days. 

The company is almost always going to know because if there's no IRB, you 

know, the physician has to get the device in some way. So they're usually in 

contact with the company for shipping and those kinds of things. So they, the 

company usually knows. But we do ask that the IRB be notified. 

(Caroline McPherson): Okay and then billing in that scenario, I assume that something that 

would have to be discussed with the manufacturer? 

Josh Nipper: I suppose. We don't typically get into the billing issues related to the devices.

(Caroline McPherson): Right.

Josh Nipper: So I don't know the best answer for you there.

(Caroline McPherson): Okay, thank you.

Coordinator: Once again, if you do have a question, please press Star 1 on your touchtone 

phone. And the next question is coming from (Carl Fisher). Your line is 

open.
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(Carl Fisher): Hi, thank you. Could you please clarify on the comments regarding the 

expectation, the applicant change or intend to change the IFU in response to 

knowledge about an adverse event for off-label use? I may have 

misunderstood the response.

Stephanie Shedd: I'm sorry. So your question is changing an indication for use based on adverse 

events and things learned?

(Karl Fisher): I thought that I heard a previous answer to a question indicated that the 

manufacturer is expected to go forward changing the IFU when they become 

aware of an adverse event related to off-label use. I just wanted to clarify if I 

hear that correctly.

Stephanie Shedd: No, I mean just to clarify. I think that statement was if the manufacturer, 

sponsor is becoming aware of off-label use, then it's on them to consider 

making that marketing application for the off-label use. But it doesn't 

specifically have to be in response to adverse events or any other type of 

event.

(Karl Fisher): And just to clarify, that's a consideration not a requirement on the part of the 

manufacturer?

Stephanie Shedd: Right, it would be in their best interest to obtain approval for that use if it's 

becoming so prevalent off-label that it should be considered to be studied or 

marketed for on label use.

Josh Nipper: We have at least one high-profile example. I won't list it but, you know, if 

you go through the archives you could probably figure it out. There's at least 

one example where there was a series of HDE devices that were being used 
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off-label, you know, huge numbers of off-label use. That were - I'm not 

saying the use was inappropriate, but they were - the HDE was being off-label 

and there was no legally marketed device. And so there was some discussion 

with the company about restricting the device. Not restricting in the sense of a 

restriction, but limiting the device, you know, to only patient that really need 

to be HDE and not the off-label.

(Karl Fisher): Thank you.

Coordinator: And once again, if you do have a question, please press Star 1 on your 

touchtone phone. The next question is coming from (Ofisinia). Your line is 

open.

(Ofisinia): Hello, thank you. Could you please advise if there are guidelines for review 

timelines with HDE supplements for changes? It seems like the timelines are 

not the same as PMA supplements.

Stephanie Shedd: Yes, that's correct. A lot of the HDE supplements will have the same 75-day 

timeline, but it may be specific to the type of supplement. For example, if it's 

a 30-day notice type of supplement under the PMA supplement guidance, then 

I believe it still carries that 30-day review timeline under HDE. But it's going 

to kind of case specific depending on what kind of supplement is coming in. 

And your OHT or the Division of Submission Support, the email is there on 

your screen could advise on this specific case.

Josh Nipper: Most are 75 days, but then there is the 30-day notice provision that apply to 

HDE as well. So, you know, real-time supplements is only PMAs. They don't 

have 180-day supplement in real time and things like that. It's pretty much all 

75 day.
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(Ofisinia): Thank you.

Coordinator: At this time, we have no further questions. I will now turn the conference back 

to Ms. Aihie.

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 webpage at www.fda.gov/training/cdrhlearn by 

Tuesday, October 29. If you have additional questions about today's 

presentation, please use the contact information provided at the end of the 

slide presentation. 

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

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immediately following the conclusion of today's live webinar. 

Again, thank you for participating. This concludes today's webinar.

Coordinator: This will conclude today's conference. All parties may disconnect at this 

time.

END