NWX-FDA OC

Moderator: Irene Aihie

08-08-16/1:00 pm ET

Confirmation # 8996213

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NWX-FDA OC

Moderator: Irene Aihie

August 08, 2016

1:00 pm ET

Coordinator: Welcome and thank you for standing by. At this time, all lines are in a listenonly mode until the question and answer session. For today's call, we will not 

be taking questions from the chat box but from phone lines only.

If you'd like to ask a question at that time, you may do so by pressing Star 

then 1 and recording your first and last name. Today's call is being recorded.

If you have any objections, you may disconnect at this time. I would now like 

to introduce your host for today's call, Ms. Irene Aihie. You may begin.

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

CDRH's Office of Communication and Education.

On June 20, 2016, the U.S. Food and Drug Administration published the final 

guidance Leveraging Existing Critical Data for Extrapolation to Pediatric 

Uses of Medical Devices providing a framework to consider extrapolating 

existing data to evaluate a devices performance in pediatric patients in 

premarket approval applications, PMAs, humanitarian device exemptions, 

HDEs, and De Novo requests.
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This guidance facilitates continued efforts to address unmet medical device 

needs for pediatric patients. The focus of today's webinar is to share 

information and answer questions about the final guidance document.

Today's presenter is Dr. Vasum Peiris, Chief Medical Officer for the 

Pediatrics and Special populations, Special Populations from the Office of the 

Center's Director here in CDRH.

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

to topics in this final guidance only. Additionally, there are other center 

subject matter experts available to assist with the Q and A of our webinar.

Now, I give you Vasum.

Dr. Vasum Peiris: Thank you very much. Thank you everybody for joining us today. As you can 

see, the title of our webinar is Leveraging Existing Clinical Data for 

Extrapolation of Pediatric Uses as Medical Devices.

My name is Vasum Peiris and I'm the Chief Medical Officer for Pediatrics and 

Special Populations with the Center for Device and Radiological Health at the 

FDA. Our webinar objectives today are basically three. We'd like to provide 

context for overview of the final guidance, describe the key changes from the 

draft guidance to the final guidance documents.

And at the end we'll have some time to answer any clarifying questions about 

the concepts in the final guidance. Let's go ahead and get started. The FDA, as 

I hope everyone realizes, dedicated to promoting timely access to safe and 

effective medical devices for all patients and we recognize the unique needs of 

pediatric patients.
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Despite this understanding and recognition of the need, currently there are 

relatively few medical devices that have pediatric specific indications and 

labeling. The final guidance proposed a framework to leverage appropriate 

data for minimizing risk to pediatric patients while maximizing access to 

medical devices indicated for pediatric patients.

And we hope that this approach may stimulate growth in a number of devices 

indicated and labeled for pediatric patients.

We begin with a little bit of the regulatory background that gives us the 

authority to consider extrapolation basically titled three of the Food and Drug 

Administration Amendments Act which we levy and call FDAAA is the 

Pediatric Medical Device Safety and Improvement Act of 2007 and we tend to 

refer to this as PMDSIA.

So PMDSIA specifically authorize the use of adult data to demonstrate 

pediatric effectiveness.

The language in the legislation specifically reads if the course of the disease 

or condition and the effects of a device are sufficiently similar in adults and 

pediatric patients, the secretary may conclude that adult data may be used to 

support a determination of reasonable assurance of effectiveness in pediatric 

populations as appropriate.

In addition, CDRH believes that extrapolation for safety is also appropriate in 

certain circumstances. So basically, what do we mean by extrapolation? And I 

intend here to clarify how we are utilizing the term extrapolation in the 

document.
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So in this guidance, extrapolation refers to the leveraging process or indication 

in a new pediatric patient population to be supported by the listing clinical 

data from studied patient populations.

So basically when existing data are relevant to a pediatric indication and 

determined to be valid scientific evidence, it may be appropriate to extrapolate 

such data for pediatric use.

One of the issues that seems to have a little bit of confusion and the exact 

definition of the pediatric age ranges, let me try to clarify that here.

So the age ranges for the pediatric subpopulations are as follows, for neonatal

basically from birth to approximately one month of age, for infants greater 

than one month to two years of age, children greater than two to 12 years of 

age, and adolescents greater than 12 through 21 years of age.

And basically this is really saying that it's less than 22 years of age so up to 

but not including the 22nd birthday. Of note, there are other definitions of the 

pediatric age ranges which are used by other centers and other government 

agencies.

As many people may understand, there are challenges to actually developing 

pediatric indications for devices and utilizing pediatric patients within study 

populations. Some of those challenges are listed here.

Basically pediatric populations may be small and (unintelligible) scattered 

potential study populations (unintelligible). Enrollment and consent 

procedures may increase trial time. There are also increased, there are also 

increased variation to the physiology, (unintelligible) physiology, anatomy, 

and human factors as compared to adults. 
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And this challenge is development of appropriate technologies. Due to many 

of these challenges, adult devices tend to get used off label in pediatric 

patients and when adult devices are used off label in pediatric patients, it 

becomes difficult to clearly understand basically accurately evaluate the needs 

for pediatric patients.

And also becomes difficult to understand accurately what issues may mitigate 

safety and effectiveness in these devices that are being utilized off label in 

pediatrics.

So why should we consider extrapolation? When leveraging relevant critical 

data, when appropriate may lead to a few hopeful benefits. We believe that it 

will lead to more devices being granted marketing authorization for pediatric 

indications, it increases availability of medical devices with appropriate label, 

labeling to support safe and effective device use in pediatric patients.

We hope it will streamline the process for establishing pediatric intended use 

claim and will enhance to encourage pediatric device development programs.

With this slide, I'd like to highlight a few of the key areas of the document 

itself.

And if you have the document with you, you can certainly refer back to this 

but any point the document is available both online and you can certainly print 

out a copy for yourself.

The document has a background section that goes into the regulatory history 

and it also discusses the purpose and potential benefits of extrapolation. The 

areas I'd like to direct your attention are the extrapolation decision process.
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So figure one is a key aspect of the document and figure one provides the 

complete decision tree which we can utilize for considering extrapolation 

decisions. The document also discusses full versus partial extrapolation and 

also discusses extrapolation for effectiveness versus safety.

In addition, the appendix of the document is a great reference and gives

examples of statistical methodology for extrapolation. The appendix 

specifically has a section that discusses potential statistical methods and also 

goes through six hypothetical and one actual example of extrapolation.

What are the objectives of the guidance? Basically, they are as we have 

indicated here, we want to increase the availability of safe and effective 

pediatric devices by providing a road map for leveraging relevant existing 

clinical data for use in premarket approval applications or PMAs, 

humanitarian device exemptions, and De Novo requests.

We want to explain the circumstances in which the FDA believes it may be 

appropriate to leverage existing clinical data to support pediatric device 

indications and labeling. 

We'd like to outline the approach FDA uses to determine whether 

extrapolation's appropriate and if so to what extent the data can be leveraged.

And we want to describe suggested statistical methodology that may be used 

to leverage the data in a way that increases precision for pediatric infants.

The guiding principles of the document. and here we'd like to just discuss 

what are the issues that really, that we have used to help guide our discussions 

and conceptual understanding of extrapolation fairly and responsibly serving 

the needs of pediatric patients is key and we're specifically looking to serve 
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those needs for devices of appropriate labeling to support safe and effective 

pediatric use.

In addition, the guidance does not change what we believe to be the threshold 

for approval or the need for valid scientific evidence. The appropriateness of 

extrapolation is also considered on a case by case basis and is guided by the 

decision tree that are referred to in figure one and we're considering these 

separately for both effectiveness and safety.

What determined the appropriateness of extrapolation? We consider three key 

factors.

First, similarity of existing adult response data and/or population 

characteristics to the intended pediatrics of subpopulation, two, the quality of 

the data, basically (unintelligible) design, data collection, and measurements, 

and three, fair and responsible support of a reasonable assurance of safety and 

effectiveness or probably benefit for HDEs.

And once again, valid scientific evidence does not change when this should, 

and the data should provide a support via valid scientific evidence. With this 

slide I'd like to highlight once again the decision tree which is again, I'll 

reference in figure one, the decision tree goes through three broad categories 

of consideration.

One is the relevance of the data. Basically, does the disease or condition occur 

in a pediatric population, subpopulation and are the endpoints in the datasets 

relevant to the intended pediatric population or subpopulation?
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We also consider similarity of response to an intervention with respect to the 

device characteristics, the disease characteristics, and the population 

characteristics.

And again, the quality of the data and we're considering quality of the data, 

the question is the adult or other population data a sufficient quality to 

demonstrate safety and effectiveness in pediatric populations or 

subpopulations? And if not, is the data a sufficient quality for partial 

extrapolation?

With respect to full and partial extrapolation, full extrapolation basically 

means that existing clinical data are used directly such as complete substitute 

for prospective pediatric clinical data.

Partial extrapolation is that existing data are combined via a statistical model 

with pediatric data sources or prospective pediatric clinical data, so partial 

extrapolation permits utilization of existing clinical data to support 

demonstration of device safety or effectiveness for use in pediatric patients 

with the expectation that some pediatric data are necessary.

And if not appropriate or sufficient to meet the threshold of valid scientific 

evidence, data will not be extrapolated. A key message that we'd like to get 

across is that extrapolation does not imply approval.

So conclusion that extrapolated data may be used does not necessarily mean 

that the data will support an approval decision. If extrapolation is deemed 

appropriate, the data would be considered in conjunction with the totality of 

evidence to either support or not support the reasonable assurance of safety 

and effectiveness or probable benefit. 
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So our next section of the webinar will include some of the key changes with 

respect to from the draft guidance to this final guidance. So the final guidance 

clarifies and explains the following, the guidance applies specifically to 

PMAs, HDEs, and now De Novo requests for pediatric indications thought.

As we noted earlier, PMDSIA states that extrapolated data may be used to 

support a reasonable assurance of effectiveness, extrapolation for safety may 

be appropriate in some circumstances.

PMAs and De Novo requests both require a demonstration of a reasonable 

assurance of safety and effectiveness. HDEs require a demonstration of safety 

and probable benefits. Extrapolated data may be particularly useful in HDE 

given the (unintelligible) of a disease or condition that's being addressed.

And one of the key takeaway points from the information presented in this 

slide is that based off these issues for review of data that provides reasonable 

assurance of effectiveness and safety, the guidance does not currently address 

510Ks and does not apply to the 510K process.

Another change from the draft guidance to the final guidance it clarifies the 

concept of borrowing strength so quantitative information provided by 

existing adult or other population data may be incorporated in one of two 

ways, either as a substitute for any potential pediatric data or as a supplement 

to new pediatric data considered in the context of statistical model.

It also clarifies how to determine similarity in device effects. Both the 

direction and magnitude of the device effects should be considered so by 

direction of a device effect, we mean that if the device has a benefit for adults, 

it should also have a benefit for pediatrics.
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The magnitude of benefits should also be similar between the populations. So 

our next steps, with respect to implementation. CDRH will use pediatric 

expertise in the evaluation of any application which extrapolation's considered 

and we're currently in the process of developing the PED's team which I know 

you all think is an exceptional acronym.

It stands for Pediatric Extrapolation for Devices team and this will be a 

centralized group with pediatric expertise. They will be available for 

consultation regarding extrapolation and we believe that this team will 

enhance consistency in standardization with respect to extrapolation decisions.

In conclusion, as I mentioned earlier, despite a recognized need, relatively few 

medical devices have pediatrics specific indications and labeling. The 

guidance proposes the framework for leveraging existing data to augment 

availability of medical devices indicated and labeled for pediatric patients.

The guidance provides clarify and predictability for device sponsors and 

enhances consistency within FDA regarding decisions involving the

extrapolation. I want to thank you very much for your time and we can now 

open up the session for questions.

Coordinator: We would now like to begin the formal question and answer session of the 

call. If you'd like to ask a question, please press Star then 1 and record your 

first and last name. Again, that's Star then 1 and record your first and last 

name. If you'd like to withdraw your question, you may press Star, then 2.

One moment for the first question, please. 

Dr. Vasum Peiris: I'm assuming now that we don't have any questions requests yet, that means 

that our, oh, looks like we do have one.
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Coordinator: We do have questions. One moment while I gather the information. First 

question comes from (Tara Beteriche). Your line is open.

(Tara Beteriche): Hi, Dr. Peiris. (Tara Beteriche) with (unintelligible). I want to thank you for 

issuing the final guidance. We appreciate the changes that were made to the 

guidance. You referenced the fact that the guidance does not cover 510Ks, do 

you have the, have you started or do you have the intention of developing 

guidance for extrapolation of adult data to PEDs for 510Ks?

Dr. Vasum Peiris: Thank you, (Tara). How are you? Thanks for the question. There obviously, as 

you mentioned, we appreciate the support in terms of completing the guidance 

but a great deal of people have worked on this so I definitely want to 

recognize all the people that have done work.

With respect to your question specifically as I mentioned, the guidance 

document does not address 510Ks specifically. We are willing to consider 

extrapolation requests in all forms but the guidance document itself does not 

address 510Ks.

(Tara Beteriche): Thank you for that explanation.

Dr. Vasum Peiris: Thank you.

Irene Aihie: We'll take our next question. 

Coordinator: Next questions comes from (Jen McDerma). Your line is open.

(Jen McDerma): Hi, thank you for that last question. It was actually kind of the question that I 

wanted to ask but in addition to that, if the device is eligible for 510K and you 

are seeking to obtain a pediatric clearance, what does FDA recommend that a 
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manufacture do to establish extrapolation of data that would, that would 

support a 510K?

Dr. Vasum Peiris: Thank you for your question. We definitely want to keep the questions 

specific to clarifying issues with respect to the guidance document itself but I 

would suggest that if you have any concerns of that nature that developing -

contacting the FDA and speaking with potentially a presubmission team 

would be beneficial.

And earlier the contact the better off you'll be with respect to clarity of 

information that will hopefully make your pathway towards approval efficient 

as possible.

(Jen McDerma): Okay thank you.

Dr. Vasum Peiris: Thank you.

(Jen McDerma): Yes.

Coordinator: Next question comes from (unintelligible) (Kim).

(Kim): Hi, Dr. Peiris, Thanks very much for holding this conference and I certainly 

want to applaud FDA for leading guidance on the, on this statement. Perhaps 

this may not be the best venue for this question but perhaps some guidance 

along these lines would be nice.

You know, device studies in pediatric patients are extraordinarily difficult to 

pursue. These are where we want to get direct pediatric data from and mostly 

because coverage for these procedures is based on state Medicaid agencies.
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What does FDA, how does FDA view and suggest ways to be able to 

incorporate patients from a Medicaid perspective based on these coverage 

decisions? Is this something that needs to come through CMS or state 

regulatory agencies?

Just lastly, in the realm of pediatric chemotherapeutic trials, all states have 

agreed that they would, that state Medicaid would cover those kinds of 

research studies but device trials are specifically exempt in most states.

Dr. Vasum Peiris: I'm not sure I follow that one through.

Coordinator: Please continue to stand by.

Irene Aihie: We apologize, we had some technical difficulty. I think Vasum is going to go 

ahead and repeat his answer for the last caller. 

Dr. Vasum Peiris: This is directed to the question that you had asked. This is my second attempt 

at this response (unintelligible) would either your more than welcome to reach 

out to me directly or you can actually reach out to DICE, the Division of 

Industry and Consumer Education and we, they can direct your questions 

appropriately (unintelligible). Thank you. 

Irene Aihie: We'll take our next question.

Coordinator: Next question is (Dave Angle). Your line is open.

(Dave Angle): My question had to do with extrapolation of data from the other end of the 

curve. Neonatal data is very similar in some ways to infants so morphology 

and physiology change at about five years of age so the PEDs become more 
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adult like after that but at the early stages, they're more like neonates. So 

neonatal data be extrapolated for the infant category of PEDs.

Dr. Vasum Peiris: Thank you for your question, (Dave). You bring up a very good point with 

respect to the changes and development perspective to physiology from...

(Dave Angle): Sorry, we're having trouble hearing you.

Dr. Vasum Peiris: Can you hear me now?

(Dave Angle): Yes. 

Dr. Vasum Peiris: Great. So you bring up a very important point with respect to the changes and 

physiology between a neonate and an infant. There are extreme variations 

with respect to critically neonates versus neonates that have gone through a 

full term gestation that has been healthy and that are developing as we 

consider quote on quote normally.

So these types of extrapolation quests will likely have to be considered based 

on as we've mentioned, a case by case basis with respect to understanding the 

distinctions and transition of physiology.

(Dave Angle): Would you accept it? Case by case?

Dr. Vasum Peiris: Sorry, could you repeat that again?

(Dave Angle): Could you accept it by cases by case? Is that what you're saying?

Dr. Vasum Peiris: Yes we're very willing to consider a case by case basis with, for extrapolation.
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(Dave Angle): Thank you. 

Dr. Vasum Peiris: Thank you.

Irene Aihie: We'll take our next question. 

Coordinator: Next question comes from (Cindy). 

(Cindy): Hello.

Dr. Vasum Peiris: Hi, (Cindy). 

(Cindy): Hi. I was just wondering if you could help me by clarifying the neonate. Is it, 

when you say from birth, do you mean gestational age too, so preemies would 

be included in that group?

Dr. Vasum Peiris: Yes. So, and that's why the definition is basically from birth and as you can 

imagine and you may be very well aware, neonates that are born at let's say, 

30 weeks gestation may have very different physiologies than a neonate that is 

born at 40 weeks gestation.

(Cindy): Correct, okay. Thank you very much. 

Dr. Vasum Peiris: You're welcome. Thanks for the question. 

Coordinator: Again, if you'd like to ask a question, please press Star than 1 and record your 

first and last name. Next question comes from (Mirage Patel). Your line is 

open.
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(Mirage Patel): Yes, how does the FDA and HHS get results from the medical devices that are 

going on here and there? This morning, I was near my kitchen and felt a 

medical devices testing me in my cardiovascular area. Where is all this data 

going to to help human services and what's the purpose of it?

Dr. Vasum Peiris: Thank you for your question, (Mirage). I can't speak specifically to your 

request but again, I want to make sure that your concerns are addressed and I 

can direct you once again to DICE, the Division of Industry and Consumer 

Education and they'd be happy to help direct your question...

(Mirage Patel): Okay.

Dr. Vasum Peiris: ...appropriately and get that information for you.

(Mirage Patel): Thank you. 

Dr. Vasum Peiris: Thank you.

Coordinator: Again, if you'd like to ask a question, please press Star then 1 and record your 

first and last name. There are no other questions. I would like to turn the call 

back over to Irene Aihie.

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

thoughtful questions. Today's webinar and transcript will be available on the 

CDRH Learn website at fda.gov/training/cdrhlearn by Tuesday, August 16.

If you have additional questions about the final guidance, please use the 

contact information provided at the end of the slide presentation. As always, 

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

concludes today's webinar. 
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Coordinator: This concludes today's call. You may disconnect at this time.

END