FDA 

Moderator: Irene Aihie

07-26-17/1:00 pm ET

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

An Introduction to Premarket Approvals

Moderator: Irene Aihie

July 26, 2016

1:00 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 of the call. To ask a 

question during that time please press star followed by number 1. 

Today’s conference is being recorded. Any objections you may disconnect at 

this time. Now I’d like to turn over the meeting to Irene Aihie. You may 

begin. 

Irene Aihie: Hello and welcome to today’s FDA Webinar. I am Irene Aihie of CDRH’s 

Office of Communications and Education. As a part of the FDA’s ongoing 

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

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

provide developers and sponsors of neurological devices, information on the 

pre-market approval process. 

The pre-market approval is the most stringent type of device marketing 

application required by the FDA, and is required because of the level of risk 

associated with Class III devices. 
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Mike Hoffmann, Deputy Director of Regulatory Policy for the Division of 

Neurological and Physical Medicine Devices in the Office of Device 

Evaluation here in CDRH will start today’s presentation. He is joined by 

members of the Division. 

Following the presentation, we will open the line for your questions related to 

information provided during the presentation. Additionally, other center 

subject matter experts will join the team to assist with the Q&A portion of our 

Webinar. Now, I give you Mike. 

Mike Hoffmann: Welcome. Good afternoon. We’re glad you could join us to hear some 

information about the PMA process. 

Just to give you a quick idea of the agenda that we’re going to go through 

today, we’re going to give some quick introductions to the PMA process, 

provide information on how sponsors and principle investigators can move 

their products to market, some information on clinical testing, non-clinical 

testing, post-approval studies, bioresearch monitoring, and then the question 

and answer session. 

Again, I am Michael Hoffmann. I’m the Deputy Director for the Division of 

Neurological and Physical Medicine Devices in the Office of Device 

Evaluation here at CDRH. 

We usually - we like to start our presentations where we emphasize everything 

which is, that the CDRH vision. And while I’m not going to read through 

each of the aspects of our vision statement, we do want to highlight the first 

one which is, that patients in the U.S. have access to high quality, safe and 

effective medical devices of public health importance, first in the world. 
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And also, to start at the beginning of what actually is a medical device? So, a 

medical device is defined in the Food, Drug, and Cosmetic Act. And it is 

defined as a device, meaning that it is an instrument; an apparatus, implement 

machine can drive its implant, etcetera, intended for use in the diagnosis, cure, 

mitigation or treatment or prevention of disease in man. And is intended to 

affect the structure or function of the body in man and, does not do so through 

chemical purposes or through chemical actions. 

So, we do have a wide array of regulatory processes, and we review a wide 

array of medical devices which have different risks and different benefits. 

And these different processes are used to match up with those different types 

of medical devices that have those different risks. And we use the most 

appropriate pathway and regulatory process for those - for each device. 

Today we’re going to be focusing on the PMA process which is highlighted at 

the top of the screen. And as mentioned before, that is the process that we use 

for the highest risk devices that we review. 

This slide gives several examples of neurological products that we regulate 

here at CDRH. They include everything from brain stimulation - deep brain 

stimulation devices to neurovascular devices to neurosurgical devices to 

diagnostics as well. 

And here we want to focus a little bit more on some of the other specific 

devices that we have cleared and approved here. And they range from clot 

retrievers, prosthetic arms. And what also wanted to note here is, we have 

ablation therapies as well that have gone through the PMA process. 
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Not all of these have gone through the PMA process. Again, we match up 

with the appropriate risks and mitigations and make sure that we use the 

appropriate pathway for each one. 

I’ll now turn it over to Tim, who’s going to talk more about the regulatory 

requirements. 

Tim Marjenin: Hi, my name is Tim Marjenin and I’m the Chief of the Neurostimulation 

Devices and Neurology Branch. And over the next few slides I’m just going

to give a very high level discussion of some of the regulatory requirements for 

PMA application. 

This is going to be fairly high level. Each individual piece could probably 

take up at least an hour. 

So just by way of explanation, more information is available in CDRH’s 

Education Page, CDRH Learns. This is also part of Device Advice which is a 

comprehensive collection of information that covers practically everything 

about our regulatory processes. 

So, let’s start with the basics, the pre-market approval statute in the regulation. 

The statute can be found in the Food, Drug, and Cosmetic Act, Section 515. 

And that’s what establishes the general requirement for PMAs in the 

regulations and the CFR that corresponds to 21CFR Part 814. 

I would like to point out that some of you may be familiar with the 

Humanitarian Device Exemption which is also - which is actually contained 

within 814. However, that’s not going to be covered as part of this Webinar 

here today. 
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Relative to other submission types, there are a lot of differences when it 

comes to PMAs. And when you’re thinking about whether it be a 510(k) or 

even a de novo, there’s a lot more that’s involved with a PMA. 

So, for example there’s a Safety and Effectiveness Standard. And we’re not 

talking about substantial equivalence here. You have to demonstrate that the 

device has a reasonable assurance of safety and effectiveness. 

There are also post-market requirements in the form of annual reporting and, 

types of submissions related to manufacturing changes. 

The review process is a little bit different too, especially when it comes to 

original PMAs or Panel-track supplements. You have a filing review which is 

something that’s not typically found on other types of submissions, as well as, 

a manufacturing review which is also not found on other types of submissions. 

Post-market requirements can also sometimes include a post-approval study. 

There are two main types - two main ways of submitting a PMA. One being 

the traditional route and one being a modular PMA. Traditionals are more 

common than the modulars. 

And so traditionals, you submit the complete application all at once to FDA, 

at which point the review begins on all of that information. 

With a modular PMA, however, the contents are broken down into various 

pieces and parts and are submitted over time. And the final module that is 

submitted would be the clinical module at which point everything gets created 

into one single, original PMA and the review continues. 
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So, modular review may or may not suit your needs. It’s going to largely 

depend on what - on whether you think it is appropriate and feasible for you. 

And really, make sure that you understand the implications and the timelines 

that are associated with modular review. And please feel free to ask questions 

if you’re not sure about anything related to that. 

There is a Guidance document. The link is here at the bottom of the slide. I 

highly encourage you to review that if you are interested in the modular 

process. 

When it comes to the actual review process of an original PMA the - some 

detailed information can be found again, at Device Advice with the link here. 

So, there are some important timeframes to consider at the front end. First 

off, there’s a Refuse to Accept review. Those of you who are familiar with 

the 510(k) process, it’s largely the same sort of thing. Although, there may be 

some slight variations in the types of things that we’re looking for. 

Filing review is something that’s not found on other types of submissions 

other than HDEs, and that happens within 30 days of receiving the file. 

And then the substantive review is ongoing up through the first 90 days of the 

review of the file after we receive it. 

So, when you’re talking about the substantive review that ends with the 

substantive interaction decision point, and that occurs by Day 90. It can 

happen before; no later than Day 90. And at that point we will either request 

some additional information or we’ll determine that there are only minor 

questions and that those can be addressed interactively. 
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So, if we’re going to request additional information by letter, then we’re going 

to outline what all of those questions are. And we’re going to tell you why we 

need - what’s missing, what needs to be changed, and why we need that 

information. 

And so, at that point the clock stops and the ball is in your Court until you 

address all of those questions. If we continue, because there are only minor 

questions, the clock doesn’t stop and we try and resolve everything 

interactively. 

So, after the substantial interaction decision point, let’s say that either we 

continue interactively or you send in a response to the letter that we sent you, 

we will work interactively with you to resolve all remaining questions. 

You should be prepared for multiple interactions about things like labeling or 

the Summary of Safety and Effectiveness Document; the SSED. And if 

there’s a Panel meeting that’s scheduled, it will likely occur after the 

substantive interaction decision point. 

Very briefly, about Advisory Committee input, better known as Panel, so this 

is defined in Part 814. And it says that, FDA will begin substantive review of 

a PMA after it is accepted for filing. And we may refer the PMA to Panel on 

our own initiative. And we will do so upon the request of an applicant unless 

we think that - well it would really duplicate what’s been done previously by 

the Panel. 

And so the Panel’s input, just to clarify, is a recommendation. It’s really no 

different in the most basic terms, from getting input internally from other 

members of the team. It’s just done much more publicly and there’s much 
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more work involved with it. So the FDA is the one that makes the final 

decision on the PMA. 

Once a PMA is approved there are a number of different types of changes that 

can be made. And depending on the type of change, the nature of the change, 

there are different supplements that are submitted and reviewed in order to get

those approved and into commercial distribution. 

Panel track supplements are closest to the original PMA. They are - they can 

involve Panel meetings, but they don’t have to. It’s really for when you’re

changing the indications. You might be adding a new indication for use to an 

existing PMA. A 180-day supplement are for fairly significant changes to an 

existing device. 

Real-time reviews are slightly less significant changes. They have their own 

guidance document. Thirty day notices are related to manufacturing changes. 

That also has its own guidance document. 

And there’s one on here that I’m not going to be able to spend a whole lot of 

time on called, Special Supplement Changes Being Affected. And basically 

that’s for labeling changes that a company wants to make to help make a 

device safer. 

So there is a guidance that covers all of the different types of modifications 

that could be done to a PMA, and the associated supplement types that go 

along with those. 

And so with that I’m going to turn it back over to Mike to talk about how 

sponsors principle investigators move their product to market. 
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Mike Hoffmann: Thank you Tim. So as Tim mentioned, there is the - one of the differences in 

the PMA process is the Safety and Effectiveness Standard. So that’s where 

we have our definition of safety. 

So there is a reasonable assurance that a device is safe when, if based on 

developed, scientific evidence, the probable benefits of the device, or its 

intended uses and conditions of use, when accompanied by adequate 

directions and warnings against unsafe use, it outweighs any probable risk. 

For effectiveness there is reasonable assurance that a device is effective if, 

based on valid scientific evidence, in a significant portion of the target 

population, the use of the device for its intended uses and conditions of use, 

when accompanied by adequate directions for us and warnings against unsafe 

use, will provide clinically significant results. 

So there are a lot of terms in there. And one of those is, valid scientific 

evidence. So FDA relies on valid scientific evidence to determine whether 

there is reasonable assurance that a device is safe and effective. And there are 

several different sources of valid scientific evidence according to the 

regulations, including well controlled investigations, studies, and objective 

trials without mass controls. 

Well documented case histories conducted by qualified experts, and reports of 

significant human experience with the marketed device. 

However, since these Class III devices which we review under PMAs are our 

riskiest devices, we rely heavily on well controlled investigation. And to be a 

well-controlled investigation the plan or protocol for the study and the report 

should include the following. 
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A clear statement of the objectives of the study. A method for selection of the 

subjects that includes the following. 

Adequate assurance that subjects are suitable for the study. Minimization of 

possible bias. Comparability between the test groups and in control groups. 

As well as, an explanation of the methods and observations of recordings and 

results that were used. A comparison of the results of the treatment or 

diagnosis with a control, so that there is a quantitative evaluation. And a 

summary of the methods of analysis, and an evaluation of the data derived

from the study including any appropriate statistical methods utilized. 

So there is a lot in the definition of a well-controlled study. And we have a 

very good system of getting feedback from FDA to determine how suitable 

your proposed investigation will be to support a future PMA. 

And the best way that we have to do that is our Pre-submission Program. And 

there’s a guidance that is, you know, in which we strongly encourage you to 

review and to take advantage of. 

I’ll now turn it over to Stacie who will begin a discussion about the nonclinical testing. 

Stacie Gutowski: Thank you very much Mike. I’m happy to discuss the non-clinical testing 

with you today. 

So non-clinical testing is also known as pre-clinical testing and it 

encompasses all testing conducted outside of a human subject. So this will 

include performance and bench testing which can include standards, as well 

as, any animal testing that you use to support a PMA. 
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Common non-clinical tests include electrical safety, battery reliability if 

applicable, if your device has a battery. Electromagnetic compatibility 

including MR compatibility. Biocompatibility, sterility and shelf-life testing, 

software testing, general, other engineering tests, as well as, GLP-compliant 

animal studies. 

And for further information regarding any of these types of tests, you can look 

at our guidance document database, as well as, our recognized consensus 

standards database to see what standards the FDA recognizes in support of our 

device submissions. 

Other performance testing can include device specific tests which may or may 

not have specific guidance documents, depending on which device you are 

submitting. And you should always check our databases as listed on the 

previous slide for information about guidance documents and standards. 

General examples of this type of other performance testing includes functional 

testing to demonstrate that the device will function as it is intended. 

Mechanical testing, fatigue testing, coating integrity should that apply to your 

device, and others as needed. 

Considerations for non-clinical testing include that the test devices should be 

in the identical final, finished form. So that means that you’d use the same 

manufacturing processes, materials, equipment, environment; etcetera. And 

the devices should also be post-sterilization processing to demonstrate that the 

sterilization that you plan to use does not alter the performance or outcome of 

the device. 

And if the test device is not identical to the final finished form, you should 

definitely provide justification as to why that has not been done. 
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Additional considerations include that you should provide full test reports. 

This may not apply when testing is completed in accordance with different 

standards. But in general, summary reports do not always provide sufficient 

details for us to review. 

Our testing and compliance with these FDA recognized consensus standards 

should always be accompanied by a Form FDA 3514 to describe your 

compliance with these standards. 

Testing to alternate standards is definitely not advised if there is a 

corresponding FDA recognized standard in the database. 

At this point I will pass it on to Sam who will talk about post-approval studies. 

Sam Raben: Thank you very much. During the review of the PMA, FDA may request a 

post-approval study be conducted as a condition of approval. This study 

request is to assure continued safety and effectiveness of the approved device. 

These studies can be clinical or preclinical evaluations and may request longterm safety and effectiveness information that could not be addressed by 

premarket data. 

Post-approval clinical studies may be new studies with a new cohort of 

patients. Or continuation of follow-up of patients enrolled in the 

investigational device exemption or IDE clinical study. 

We strongly encourage applicants who are conducting a pivotal study to 

consent subjects for long-term participation in the study such as five years, in 
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the event that long-term safety and effectiveness data may be needed as a 

condition of approval for the PMA. 

Before a PMA is approved, and during the review phase, if a post-approval 

study is needed, FDA will provide the applicant with the general framework 

for the design and endpoints of the post-approval study. And concurrence will 

be obtained from the applicant agreeing to this general framework for the 

post-approval study. 

The full and complete post-approval study protocol can be either, developed 

and agreed upon by FDA and the applicant during the PMA review process if 

there is time or, this information can be submitted after the PMA is approved, 

through a PMA supplement. 

If a post-approval study is warranted, development and agreement on the 

study protocol should be provided by both FDA and the applicant. A postapproval study protocol should include the following. 

A background section that includes the regulatory history, device description, 

communication for use. The purpose for the proposed study, the objective and 

hypothesis that will be evaluated. The trial design, the treatment population 

which should include information regarding the inclusion, exclusion criteria, 

as well as, the proposed comparative group. 

A sample size calculation with accompanying statistical justification based on 

the study hypothesis, primary and secondary endpoints, the length of followup, including the follow-up schedule, baseline, follow-up assessment, a 

description of the data to be collected in the collection procedure, a statistical 

analysis plan, and the data collection forms such as the Informed Consent 

form, IRB Approval form, and the Case Report form. 
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A summary of the reported requirements for the interim and final reports. 

And finally, the study milestones and the outline of the study timeline. 

For post-approval studies the applicant will submit interim reports every six 

months for the first two years and then annually, thereafter. The due date of 

these reports is based on the original approval date for the PMA. 

These reports should contain an update of the study progress, a summary of 

the safety and effectiveness data, along with an interpretation of the study 

results to date. 

At the conclusion of the study the final report should be submitted no later 

than three months after study completion. Study completion is defined as, all 

subjects having completed follow-up. 

If you fail to complete a post-approval study, this may result in a withdrawal 

of the approved PMA. If there are limitations or a particular scenario under 

which it is determined the study cannot be completed, this information should 

be communicated to FDA as soon as possible, either through an interim report 

or a PMA supplement. 

For additional information regarding post-approval studies, we provide the 

following links. The first is, FDA’s guidance regarding post-approval studies 

and posed by PMA orders. This guidance document discussed the study 

protocols, interim report procedures, and final report documentation. 

There is also logistical information that may be beneficial during the 

development and conduction of the study. 
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The second link is the post-approval study public database. This database 

provides general status information regarding post-approval studies ordered 

since January 1, 2005. 

And then finally, FDA - the final link is for FDA’s Post-Approval Web site 

which provides some more general information regarding post-approval 

studies, as well as, some additional links and resources. 

And then with that I will turn it over to Commander Bah. 

Isatu Bah: My name is Isatu Bah. I’m with the Division of Bioresearch Monitoring. 

The BIMO Program is a comprehensive agency-wide program of on-site 

inspections and data audits designed to monitor all aspects of the conduct and 

reporting of FDA regulated research. 

Clinical studies are conducted all over the world. We receive data from 

foreign countries for pre-market approval application. We therefore conduct 

domestic, as well as, foreign inspections. We conduct inspections anywhere 

the device study records are maintained. 

We have these three objectives and one way we meet them is through 

inspections. The purpose of inspections is not to find errors, but to gain 

confidence in how the study was conducted. And to gain confidence in the 

accuracy, reliability, and integrity of the submitted data. 

Its involves interview with the site personnel, onsite evaluation of source 

documents, and the evaluation of the systems in place to protect human 

subjects, produce quality data, and to comply with applicable regulations. 
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For PMAs, the FDA investigator who is doing the inspection will do a 

sampling of data and compare the data line listings submitted by sponsors in 

the PMA to the source documents and the case report form for accuracy and 

completeness. 

These are the lists of regulations that are applicable to drug, devices, as well 

as, biologics. 

These regulations are applicable just to device clinical studies. 

These are some of the information that BIMO reviewers will review and 

consider when we do site selections for inspections. We also collaborate with 

the review divisions and the Office of Surveillance ad Biometrics when we do 

site selection. 

For PMAs, we have 30 to 45 days to issue inspection assignments. The FDA 

investigator at the District Office will usually contact the site personnel and 

notify them of the inspection between 3 to 5 days for routine inspections. 

Please note that for “For Cause” inspections, we don’t preannounce the 

inspection. The FDA investigator may just show up on the site. 

When the investigator arrives at the site, they will issue what is called the 

Form FDA 482, which is the Notice of Inspection. They will interview site 

personnel about their responsibilities in the conduct of the study. 

They will review the study records and conduct data audit, comparing the data 

line listings submitted in the PMA to the source documents and case report 

forms. 
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If there are any deviations from the regulations, the FDA investigator will list 

that on the Form FDA 483 at the completion of the inspection. And they will 

discuss verbally, minor observations that may not be too egregious to list on 

the Form FDA 483. 

These are some of the documents that the FDA investigator reviews during the 

inspection. The link at the bottom of this slide is for the Compliance Program 

Guidance Manual which is the CPGM. 

The FDA investigators usually use this CPGM. It provides them with 

instructions to evaluate industry activities when conducting inspections. 

This CPGM has been made available to the public through the Freedom of 

Information Act. Sponsors and industry can use this to prepare for future 

FDA inspections. 

If a Form FDA 483 is issued, we usually recommend that the firm provide a 

response to the FDA investigator during the inspection or they can mail or 

forward it to the investigator within 15 days after the completion of the 

inspection. 

We also highly recommend that you document any corrective and preventive 

actions. And make sure to include documentation of staff trained including 

dates and signature of staff that completes the corrective and preventive 

actions. 

As well as, include the expected implementation dates for corrective and 

preventive actions. 
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At the completion of the inspection, the FDA investigator usually completes 

an establishment inspection report which is the EIR. 

The FDA investigator will forward the EIR, the Form FDA 483, if it was 

issued, and any supporting documents to BIMO. BIMO will review the 

supporting evidence, the EIR, and the response if it was received within 15 

days. And the BIMO reviewer will then determine the final compliance 

action. 

These are the compliance classifications. For NAIs, BIMO will issue what we 

call, a Firm in Compliance Letter to the firm. For VAIs, BIMO will issue an 

Information Letter. And for official action indicated, we might issue an 

untitled letter, a warning letter, and we might recommend sanctions. 

There are usually many opportunities for BIMO to collaborate with industry 

during pre-submission meetings, so that we can guide industries to conduct a 

successful study. 

So please reach out; contact us during pre-submission meetings, and we can 

provide some guidance. And this is our information. You can reach us by 

phone or by email. Thank you. I now have Vesa. 

Vesa Vuniqi: Thank you. My name is Vesa Vuniqi. I’m a Reviewer in the Division of 

Manufacturing and Quality, Office of Compliance, CDRH. During this 

presentation I’ll be giving information on the manufacturing section of the 

PMA. 

As an overview, Original and Modular PMAs, Site Changes, and 30 day 

Notices require manufacturing information for review. Some of these 
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submissions may also require pre-approval inspections. So I’ll go over that as 

well, during this presentation. 

Now I’ll be discussing Original and Modular PMAs in more detail. First I’d 

like to discuss the major steps in the review of the PMA manufacturing 

information. 

The manufacturing information is received in the Office of Compliance, in 

CDRH, and it is assigned to a Reviewer. This information is reviewed 

according to 21CFR Part 814 and Part 820. 

Once a desk review is complete, if a determination for an inspection is made, 

the assignment is sent to the ORA, the Office of Regulatory Affairs. 

ORA is then responsible for conducting inspection and complete the 

inspection report. That report is then sent back to CDRH for final review and 

classification. 

There is a guidance document which is referenced on the slide that outlines 

the information that should be submitted for review. Primarily, this asks for 

submission of procedures and records for some of the subsections. 

The information required is consistent with Part 814 and Part 820 and is 

divided into two sections, Design Controls, and Manufacturing Controls. 

In order to facilitate the review process, it is recommended that the following 

be submitted with the application. A cover letter, overview of what the 

manufacturing section contains and how it is organized, device description, 

overview of the manufacturing facility, copy of the Quality Manual, and the 

list of standards used in the manufacturing process. 
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As mentioned before, the guidance primary asks for procedures related to 

major sections for design and manufacturing information which may include 

procedures related to complaint handling and CAPA. 

It is also helpful, in addition to procedures, to include narrative summaries of 

the procedures, and then reference to the sections within the procedures or the 

location of the attached procedures. 

Manufacturing information is required for all finished device manufacturing 

sites, including sterilization sites. So it is recommended, separate volumes be 

submitted, including procedures for each site. 

CDRH Office of Compliance reviews the manufacturing section of the PMA 

according to the guidance document. If, during the review process, 

deficiencies are identified related to the quality system, they are 

communicated back to the applicant via a formal deficiency letter or email for 

a more interactive review process between the reviewer and the applicant. 

Pre-approval inspections may be conducted at sites manufacturing finished 

devices, critical components, or sites performing sterilization. It is important 

to note in the submission, the date when the sites are ready for inspection as 

they are scheduled on or after that date that is identified by the applicant. 

If however, the site is not ready for inspection, this may result in delayed 

approval of the PMA. This would be considered approvable pending GMP, so 

it’s not a good position to be in. And so it should be avoided if possible.

A determination for inspection is made based on instructional history, and 

whether a similar process was covered during the previous inspection 
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conducted at the manufacturing facilities. This applies for both domestic and 

foreign facilities. 

Now I’ll move on to site change supplements. Site changes are appropriate 

when sites are not approved as part of the original PMA or PMA supplement. 

Or they were approved as part of the original PMA but, for the performance of 

different manufacturing activities. 

There is a draft guidance of those previously issued for comment. It is very 

helpful and provides more details of when a site change is appropriate, and 

prediction of when an inspection would most likely be required. 

The information required for a site change is similar to the original PMA 

manufacturing information. However, it does not require design control 

information since the design would not change. 

It is important to provide process validation testing or state when the 

validations will be completed and when the site is ready for inspection. 

Site changes are also subject to pre-approval inspection and follow the same 

time goal as the Original PMA. The same as the original PMAs, deficiencies 

related to quality system regulations are conveyed to the applicant via a 

formal letter or an interactive review process. 

Now I’ll give more information on 30-day notices. 30-Day Notices are 

appropriate when there is a manufacturing process change that would affect 

the safety or effectiveness of the device. This may include changes to the 

manufacturing procedure or changes to the manufacturing process or method 

of manufacture. 
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There is a guidance document that is very helpful and provides more details 

on when a 30-day notice is appropriate. And that is referenced on the slide. 

Some examples of when 30-day notices are appropriate include, changing a 

manual process to an automated process. Changes to a cleaning process 

which is performed in manufacturing of the device. Change in machining 

lubricants, sterilization cycle, a change in sterilization cycle, or sterility dose 

auditing. Addition of manufacturing space or, addition of manufacturing lines 

at the same facility. 

Changes that are not appropriate for a 30-day notice include addition of a new 

manufacturing site, or moving the manufacturing site. Changes a device 

design which includes changes to the design specifications. Or material 

changes and minor changes that do not affect the safety or effectiveness that 

are annual reportable. 

After the review, an acceptance of 30-day notice can be made within 30 days. 

Or in cases when additional information is required, it can be converted a 135 

day supplement. 

It is common for deficiencies to be conveyed. But it’s not important - but it is 

important to note, that the conversion can be done with or without 

deficiencies. After the review of the information within 135 days, the 

determination is made for approval or not approval of the supplement. 

The information that should be submitted for a 30-day notice is a clear 

description of the change summary of the data or information supporting the 

change, statement that the change was made under requirement 520 of FD&C 

Act and, 21CFR Part 820, the reason for change including description and any 

adverse event or any failures being addressed. 
FDA 

Moderator: Irene Aihie

07-26-17/1:00 pm ET

Page 23

And now I’ll hand it over to Mike for closing remarks. 

Mike Hoffmann: Thank you. Just a few quick items. So as mentioned before, we brought up 

the pre-submission process. It’s a great way to get some feedback on your 

specific device; your specific issue that you would like to discuss with us so, 

it’s very targeted. 

You can use it to get feedback on an investigation that you’re planning to 

conduct. You can also get information on an approach that you’re going to 

take for a future PMA or a PMA that you’re going to be submitting very soon. 

We’d also like to point out that for information on some of the other 

regulatory processes and other items related to neurology and physical 

medicine devices, we have an article that’s published in Neuron that we 

encourage you to look at, as well as, information about neurological devices 

from our FDA Web site that we have a specific link for here. 

And we’d just like to leave you with, you know, basically what this is all 

about. We have several investigators; developers who are looking to bring 

high quality devices to patients. And they are the focus of what we do here. 

And what you all are doing as well. And thank you very much for your time. 

Irene Aihie: Thank you. We’re going to go ahead and open the line for questions. Just as 

a reminder, we will only be taking questions by phone. However there are a 

few questions here that have been typed in. I’m going to read those questions 

and see if anyone in the room would be able to answer them. But moving 

forward, we’re only going to be taking questions by phone. 
FDA 

Moderator: Irene Aihie

07-26-17/1:00 pm ET

Page 24

Okay, the first question that we have that was typed in was, what’s the 

difference between RTA and billing review or filing review? 

Tim Marjenin: This is Tim Marjenin. So the difference between acceptance reviews and 

filing reviews, acceptance reviews is something that was introduced with 

PMAs back in MDUFA III. It didn’t used to be part of the review process.

And so it used to be that there was this filing review and then the substantive 

review. Really what the difference is, is that for acceptance, what we’re 

looking at is whether the file is administratively complete. And that’s true, 

whether it’s a PMA or it’s a 510(k). 

A filing decision is really looking at whether the data are consistent with the 

protocol, the final device design, and the proposed indications. So it’s almost 

like a light version of a substantive review. It’s a little bit more targeted at 

something that you would along find with PMAs. 

Irene Aihie: Okay. The next question here is referring to Slide 14. They said, FDA will 

issue a, refuse to accept within 15 days of receipt which is different from the 

PMA review process Web site. The link you provided states 45 days. 

Was this a change that was adapted because of 21st Century Cures Act? 

Tim Marjenin: So, with the PMA, they still go through the acceptance review, and that’s 

going to be done 15 days after the PMA gets logged in. Meaning that it’s 

passed through eCopy and it’s actually been logged into the system. 

And then within 30 days after that, we will conduct the filing review. So 

there’s still two parts to the process. The first one being the acceptance 

review which happens within 15 days. And then 30 days following - within 
FDA 

Moderator: Irene Aihie

07-26-17/1:00 pm ET

Page 25

30 days following the acceptance review or 45 days total, after the receipt of 

the PMA, that’s when we would finish the filing review. 

Irene Aihie: Thanks Tim. And then our final online question before we go to the phone, 

can you describe how the PMA process for a Class II device would differ 

from what was presented here? 

Mike Hoffmann: This is Mike Hoffmann. It would differ quite a bit because if it’s a Class II 

device, actually we have a different process for those devices. 

So one of the earlier slides we mentioned that there are a host of different 

regulatory processes. And depending on what the risk of the device is, we 

will be able to find the most appropriate process and pathway for that device. 

For a Class II device, the most often used process is our premarket notification 

or 510(k) process. There is more information about that in our Device Advice 

on line. But that is a different process. 

Irene Aihie: Thank you Mike. Operator, do we have any questions on the line? 

Coordinator: Not at this time. But as a reminder, please press star 1 to ask a question. 

Irene Aihie: We’ll give it a few seconds for folks to come in. 

Coordinator: Our first question comes from (Frances Dillon). Your line is open. 

(Frances Dillon): Hi, I have two questions. In regard to the refuse to accept period of 15 days, 

is this also applicable for a 30-day notice? And so would that mean that the 

30-day notice period starts after the 15 day period? 
FDA 

Moderator: Irene Aihie

07-26-17/1:00 pm ET

Page 26

And the second question is, is there any guidance regarding the submission 

content for a 180-day supplement? 

Tim Marjenin: This is Tim Marjenin again. So I don’t believe that there is a specific 

guidance document for 180-day supplement. In general I would tend to say 

that really, it needs to contain sufficient information to support the change 

that’s being made. 

So all of the testing that’s being conducted, the protocols, the results, 

summary reports, any associated labeling if it’s something that would be 

changing the labeling; those sorts of things. 

Then as always, it’s the sort of thing where if you have questions about 

whether or not you should be including a piece of information or you’re just 

not sure about what you should be including, please feel free to reach out to 

somebody within the Division. Because that can be a simple 10-minute phone 

call where you just kind of quickly say, well here’s what I want to do. Here’s 

what I’m planning on providing. Does that sound about right? And we can 

help guide you. 

As far as the RTA process, the RTA process applies to two types of PMA 

submissions. One is the original PMA and the other one is the Panel-track 

supplement. 

All of the other supplements - all the other available PMA supplements do not 

have an RTA review. 

(Frances Dillon): Okay, thank you. 

Coordinator: The next question comes from (Richard Russo). Your line is open. 
FDA 

Moderator: Irene Aihie

07-26-17/1:00 pm ET

Page 27

(Richard Russo): Thank you. Does the branch have any guidance or history with removable 

devices in contact with the CNS? 

Irene Aihie: One second while we get that answer for you. 

(Richard Russo): Thank you. 

Mike Hoffmann: This is Mike Hoffmann. I don’t think we can talk about specific submissions 

or specific devices at this time. I’m trying to think offhand. But that might be 

a better question that we can have either with (unintelligible). Or if you want 

to follow up with us after the Webinar, that’s something that we can address 

off line. 

(Richard Russo): Okay, thank you. And a second question if I could, will the agency, except 

for let’s say a spinal cord application, the same data that it would accept for a 

cranial application? Or will you require different data for those two different 

anatomical sites? Biocompatibility data; excuse me, to be specific. 

Mike Hoffmann: So this is Mike Hoffmann again. That’s probably a question that’s best 

reserved for a Q-submission. In general, when we are looking at I would say, 

the context of use or where a device is being used, we’ll look at all the - any 

of the differences. And if there are similarities, we can see what we can do. 

But the best would be to use a Q-submission to get that information. 

(Richard Russo): Thank you very much. 

Coordinator: Our next question comes from (Chey Jerrell). 
FDA 

Moderator: Irene Aihie

07-26-17/1:00 pm ET

Page 28

(Chey Jerrell): Yes, thank you. I just have a question in regards to possible permeation of the 

significant risk IDE PMA pathway. It’s more of a just an intellectual - a 

though experiment. 

But I’m assuming it would be possible that you could have a significant risk 

IDE that ultimately could lead to a 510(k). Or is it the case that every 

significant risk IDE, ipso facto, will require a PMA? 

Tim Marjenin: This is Tim Marjenin. So we actually come across that sort of thing all the 

time. And the short answer is, no. Just because it’s a significant risk device 

and requires an IDE that does not automatically imply that it’s going to 

require a PMA. 

(Chey Jerrell): Okay, thank you. 

Coordinator: Our next question comes from (Patrick Gora). Your line is open. 

(Patrick Gora): Thank you. I’ve just got a quick question about manufacturing inspections. 

Our device is going to be a drug device combo. And so we’re going to 

actually be going (unintelligible) photodynamic therapy device. 

So I know you were talking about inspections at the manufacturer for the 

device portion. I don’t know if you can answer this, but would that also 

include probably inspections at the drug manufacturer as well? 

Vesa Vuniqii: I think that’s slightly different. Because I think we’re now talking about 

combination products. I’m not very familiar on how CDER - how they 

determine how they’re going to conduct inspections or when they conduct 

inspections at their manufacturing sites. 
FDA 

Moderator: Irene Aihie

07-26-17/1:00 pm ET

Page 29

Part of the combination product, I can tell you is that they consult CDRH for 

the device portion. And during that review we may recommend to CDER that 

they do part of that inspection. That they also cover medical device 

regulations. 

(Patrick Gora): So yes, so you would - for your site then you would recommend or not 

recommend for whatever reason, to do the inspection of the device 

manufacturer. 

But do you guys have any experience on the combo product Panels where 

they would also do an inspection at the drug manufacturer? Or would that be 

something that was very common or automatic? 

Vesa Vuniqui: Again, this would be for the combination product manufacturer. So if there’s 

a drug manufacturer by itself, then there’s no devices - devices would not be 

covered during that inspection. 

(Patrick Gora): Okay. 

Coordinator: Our next question comes (Deanna Hunt). Your line is open. 

(Deanna Hunt): Hi, thank you. I have two questions. The first, with regard to novel devices 

that are categorized as Class III devices by default, are these automatically 

considered significant risks? And would they require an Advisory Panel 

typically? 

Tim Marjenin: So if I’m understanding your question correctly, and feel free to correct me. 

When you’re talking about a novel device, it used to be back in the day, that it 

would automatically be Class III. 
FDA 

Moderator: Irene Aihie

07-26-17/1:00 pm ET

Page 30

And so part of the issue that we came across was that not everything would be 

- would rise to the level of requiring a PMA due to the risks associated with it 

which is, why we have the de novo process for things that have less risk. 

So I mean the - a novel device could be PMA or it could be a de novo, 

depending on the level of risk that’s involved. And again, that’s the sort of 

thing that’s best discussed in the context, or at least introduced in the context 

of the Q-sub. And possibly in informational meaning just to come in and talk 

about what it is; what you have, and how it may be similar or different to 

other things that are out there. 

As it relates to Panel input, historically we have tended to take first of a kind 

devices that are submitted via the PMA process to Panel. I believe that’s still 

generally true. 

Other times we - if it’s the third or fourth one, we may or may not take 

something to Panel. Again, it’s a matter of whether we’ve gotten sufficient 

input from the Panel in the past. On the same sorts of issues, there could be 

something unique about a new PMA, even if it is the third or fourth of a kind, 

that might necessitate take it to Panel. 

That’s the sort of thing that if there is the - if and when there is potential for 

taking something to Panel, that is something that’s discussed with the sponsor. 

It’s not all of a sudden out of the blue hey, there’s a Panel Meeting and you 

should show up. 

It’s - we recognize and understand that there is a lot of work that’s involved. 

And it’s not a trivial decision to take something to Panel. So it’s something 

that’s discussed at length. 
FDA 

Moderator: Irene Aihie

07-26-17/1:00 pm ET

Page 31

(Deanna Hunt): Okay, perfect. And the follow-up question to that, assuming we’re dealing 

with a PMA device and putting together an IDE pre-submission, would it be 

possible or recommended to potentially combine you know, the different 

aspects of a study risk determination. A determination meeting; an agreement 

meeting, all within maybe a top level Q-sub pre-submission? 

Or that the agency recommend to keep those individual elements broken up 

and keep them separated? 

Tim Marjenin: I would say that in general, it may be possible to fold in aspects of a risk 

determination discussion into a traditional Q-sub. However, the output of a 

traditional pre-submission is not going to be the sort of thing that you could 

take back to your IRB and say hey, FDA has said that we have a nonsignificant risk device, for example. So it depends on what you need as far as 

that’s concerned. 

If you have more specific questions about that sort of thing, once again your 

best bet is to reach out to somebody with some more specifics and we can 

give you some more targeted feedback than we might be able to provide here. 

(Deanna Hunt): Excellent. Thank you. 

Coordinator: Our next question comes from (Michael Nelo). 

(Michael Nelo): Hi. Thanks for the presentation. I just had a quick question. Does the Neuro 

Division have a stance on the amount of OUS versus US clinical data to 

support PMAs? 

Tim Marjenin: We can and do accept OUS data. The amount - the relative amounts of data 

that’s OUS versus within the US, that’s not really something that’s spelled out 
FDA 

Moderator: Irene Aihie

07-26-17/1:00 pm ET

Page 32

anywhere in guidance saying that you need to have X percentage collected 

from within the US versus collected OUS. 

I think really it’s a matter of just ensuring that there’s sufficient comparability 

between the two populations. And once again, running theme, whenever you 

have those sorts of issues and you have - and you are thinking about 

submitting a large proportion of OUS data in a PMA, it really is a good idea to 

come in and talk to us first, just to see whether there might be any particular 

issues that you need to consider when you’re preparing a PMA application. 

(Michael Nelo): Thanks Mike. 

Coordinator: And our last question comes (Gregar Srivas). Your line is open. 

(Gregar Srivas): Yes, (Gregar Srivas) speaking. We are doing MR safety testing, 

(unintelligible) Germany. And MR safety testing (unintelligible) we have a 

lot of active implant customers over from the new area. And quite often we 

recommend to do a test plan in advance. 

And because the topic is quite complicated, I have heard from FDA already, 

and also we recommend in the very beginning to speak to FDA. And my 

question is, how do you propose recommending (unintelligible) to do this? 

Because quite often our clients are saying no, we don’t like to speak to FDA 

in advance because they put more homework on our top than we may be 

actually have. 

But we see quite often that they’re doing a circle in approval if they do not use 

the full test plan and (unintelligible) right now. 
FDA 

Moderator: Irene Aihie

07-26-17/1:00 pm ET

Page 33

Mike Hoffmann: And so this is Mike Hoffmann here. And so I would strongly advise that 

people come and use the pre-submission process. 

I have heard that concern before about perhaps getting information you may 

not want to hear. I guess the real question tends to be, would you rather hear 

it beforehand when you have a chance to make some changes? Or would you 

rather hear it after testing has been completed? 

And so I think after we explain that, I think people tend to have a better idea 

there. Because if you’ve already done the testing and we have some concerns 

with it; it may require retesting which may be more resources and more time. 

Tim Marjenin: And this is Tim Marjenin. I’ve heard from other companies as well, that they 

do see the value in building some time into the development process to check 

in with us as necessary just because, as Mike was saying, it’s far easier to 

figure out the type of testing that you need to do before you’ve actually done 

it. 

And so the other aspect to that too is that, as much as we’d like to push the 

pre-submission process, and as much value as it can provide, it’s not always 

necessary. And it’s the sort of thing where if you’re kind of on the fence as to 

whether it might be a worthwhile use of everybody’s time -- yours and ours --

you can reach out to one of us and say hey, we’re thinking about this testing. 

And if you’re doing it the same way as it’s been done in the past; you’re doing 

it to the standard. You’re not really doing anything different. You don’t 

really have much in the way of questions, we may say well, maybe that’s not 

going to be the best use of your time, necessarily. 
FDA 

Moderator: Irene Aihie

07-26-17/1:00 pm ET

Page 34

On the other hand, you could say well, we’re thinking about doing it this way. 

And it is a little bit different. We think it might be okay. What do you think? 

And so in that case we might say well, it’s kind of up to you. It may be 

worthwhile to come in and have a chat with us about it first. If you think that 

you’ve got sufficient information from other sources, and you can adequately 

justify your position and why you believe that what you’re doing is an 

appropriate approach relative to what else has been done, that’s fine too. So, 

it depends. 

(Gregar Srivas): Okay, thank you. So in total you think it’s a good chance to save time on both 

parts, especially if there’s a new device. And maybe the standard bandwidth 

of the standard word is developing itself in the meantime as well? 

Tim Marjenin: Yes, I would say so. 

(Gregar Srivas): Okay, thank you. 

Coordinator: We have no further questions. I’ll now turn the call back over to Irene. 

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

thoughtful questions. Today’s presentation and transcript will be available on 

CDRH Lean Web page at www.fda.gov/training/cdrhlearn, by Thursday, 

August 3. 

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

contact information provided at the end of the slide presentation. 
FDA 

Moderator: Irene Aihie

07-26-17/1:00 pm ET

Page 35

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 the live Webinar. Again, thank you for participating. This 

concludes today’s Webinar. 

Coordinator: thank you for your participation in today’s conference. Please disconnect at 

this time. 

END