Welcome to the De novo Program. My name is Elias Mallis, Director of the Division of Industry and Consumer Education at FDA's Center for Devices and Radiological Health. For this session, we'll review the basics of the De Novo Program. During the course of this presentation, we'll cover several learning objectives. First, you'll learn to be able to describe the legal and regulatory basis for the De Novo Program. Next, we’ll review and describe the de novo submission process. Next, we’ll assemble the materials that will lead to a good quality de novo submission, and finally, you’ll learn to be able to identify the resources useful in preparing a de novo application.

So to frame this conversation, let's start with the definition - what is a de novo? It's a classification process that uses a risk-based strategy. It applies to new, novel devices whose type has previously not been classified. It’s for devices that would otherwise be classified into Class III, and provides a means to classify into Class I or II. For de novo, it is an application sent to FDA by a medical device sponsor. If the de novo is granted, it establishes a new device type, along with a new classification, regulation, necessary controls and a product code. If a de novo is granted, the device is eligible to serve as a predicate for new medical devices, where appropriate, within the 510(k) process.

So to understand the de novo program, it's important to go back to the beginning of the medical device regulations, and that would be 1976, with the enactment of the Medical Device Amendments. Two major activities occurred during this time. First, we refer to section 513 of the FD&C Act. Within this Act, we described the classification of medical devices according to the level of risk – it’s a risk-based approach - and we have Class I,  II and  III levels of risk. Class I applies to general controls, Class II refers to general and special controls, and for Class III, these are reserved for general and premarket approval controls. A reference for regulatory controls may be available at this website.

During this time, all medical devices that were known to exist at that time were classified into Class I, II or III. For Class III, again, these are devices that require premarket approval, and these were reserved for devices at the highest level of risk. This was reserved for devices where we were unable to rely on general and/or special controls in order to regulate them under lower classification. So once we classified all devices that were known at that time, we also have new devices that may be developed over the course of the regulations of history. This pertains to section 513 (f)(1). This is reserved for post amendment Class III medical devices.

So for a new device that was not in place at the time of the medical device amendments, this was a new device. And it refers to devices not equivalent to Class I or II devices. These were automatically classified into Class III regardless of level of risk for that product. So with the De novo program, this attempted to fill a gap within the automatic classification of devices into Class III. As result, section 513 (f) (2) was established and enacted in 1997 under the Food and Drug Administration Modernization Act.

Section 513 (f)(2) established the de novo classification process. This is also known as the evaluation of Automatic Class III designation. This provided FDA with the regulatory authority to classify devices that were automatically classified into Class III, per section 513 (f)(1). Again, these are new devices. It provided FDA with the ability to classify Class I or II using the criteria of section 513 (a)(1), A& B. It is important to note this excludes devices already classified into Class III - both those at the time of 1976 Medical Device Amendments, as well as devices that were eventually classified into Class III.

In brief, the de novo process, as of the 1997 law, was a four-step process. The first step was that the sponsor would submit a 510(k) or a premarket notification. Next, FDA would issue a final 510(k) decision of Non-Substantial Equivalent due to no predicate. Next, the sponsor then submits the De novo request and finally, the last step, FDA decides whether to classify the device from Class III to either Class I or Class II with a new classification and regulation.

In 2012, we made further modifications to the De novo Program. This was done under the Food and Drug Administration Safety and Innovation Act, or FDASIA . So what changed was the ability to allow a sponsor to not submit a 510(k) prior to the de novo request. In addition, the time frame for review of a de novo was established at 120 FDA days. The purpose of this was to help streamline and increase efficiency of the de novo process. So what didn't change was that de novo only applied to devices that were considered new devices, that is, those devices that would be classified under section 513 f1 of the FD&C Act. Sponsors still had the opportunity and option to submit a 510(k) first. That was the option under FDAMA, from 1997. Importantly, the intent and decision making threshold for de novo was unchanged.

So in 2012, the de novo process was more streamlined, and it was a two-step process. The first step is that the sponsor may submit a de novo request directly, and the second step is that FDA would then decide whether to classify the device from Class III to Class II or Class I for the new classification and regulation. We have several resources that describe these processes.

After the passage of FDAMA, the FDA issued a De novo guidance in 1998, and this describes the De novo process since that time. What is important to note, is that due to the enactment of FDASIA of 2012, some acts of this guidance may no longer be current. More recently, after the passage of FDASIA, we issued the 2014 de novo guidance in draft. Now here on this slide we have links to both of these guidances. For this 2014 de novo draft guidance, this was published on August 14 of this year. This reflects the proposed policy and procedures to implement the changes to the de novo program from FDASIA of 2012. Keep in mind; because this is a draft guidance, it is not to be implemented at this time. If finalized, it will replace the 1998 guidance, and there is a 90-day public comment period for review and comment of the draft guidance.

So what are the major items of the draft guidance of 2014? Well, this guidance explains the changes to FDASIA and the FD&C Act. Specifically, to allow the alternate pathway that does not require the submission of a 510(k) prior to the de novo request. Again, the time frame for review was established for 120 FDA days.

We now describe the decision options for a de novo. We either grant the de novo, or decline the de novo. The guidance describes and goes into some detail of the pre-submission meeting process and we introduce a new term. So for a de novo that is not preceded by 510(k), we refer to this as the “direct de novo”.

Let's go through the de novo submission process. As result of both the original law and the modified law of FDASIA of 2012, we now have two pathways available.  I'll refer to them as Pathway #1 for 510(k) then the de novo, or Pathway #2 or the “direct de novo”. So for Pathway #1, we start with the 510(k) de novo. The best means to use this is when you believe you have a suitable predicate for your device. You have a new device, you believe you have a viable predicate, so this is the option to consider using.

The first step is that you submit your 510(k) submission. Keep in mind, this should be a comprehensive, complete 510(k) submission. This is where you are doing your best job to demonstrate Substantial Equivalence to the predicate device you believe is appropriate for your new device.

The next step is that FDA reviews your 510(k) submission. Now in this case, FDA will make the NSE decision, Not Substantially Equivalent decision, due to lack of  a predicate. By lack of a predicate, what we mean is that the proposed predicate device that you proposed does not have the same intended use and technological characteristics as your new device. As a result, FDA is issuing an NSE decision.

Now in the NSE letter that you may receive if FDA believes, we believe, that your product is a de novo candidate, we will indicate that in the NSE letter.

This is based on the risk-benefit profile, not the adequacy of the evidence or data that you submitted in your 510(k).

The suggestion for de novo is not binding by FDA, and conversely, if we don't include this suggestion in your NSE letter, you still have the opportunity to pursue a de novo if you believe you qualify. Once you received an NSE, you then may follow up with the de novo application. It would be important to reference the prior 510(k) submission that you submitted prior to this de novo. In this de novo application, you would also provide additional evidence to demonstrate the safety and effectiveness of your new device as appropriate.

Importantly, if there are any differences between the 510(k) device and that of the de novo, you would want to characterize those differences in evidence gaps that may warrant additional testing and safety and effectiveness information to support your de novo.

Within your de novo application, there are several key things you will also be doing regarding characterizing the device and the risk to health. The first step is to characterize the risk to health associated with the use of the new device. Then characterize how those risks may be mitigated. Next, provide a rationale for why the device does not fit into any existing regulation, and if you propose Class II classification, you’d also describe the special controls to mitigate the risk to health. I referred to special controls earlier in this presentation. Finally, FDA will then review the de novo application.

During the review, we may interact with you and ask for additional information to clarify your device and perhaps additional testing. Ultimately, we’ll render a final de novo decision. We will either grant the De novo or decline the de novo. This is Pathway # - 510(k), then de novo.  

Now you have another option, Pathway #2, the direct de novo. When to use this makes most sense if you believe you don't have a suitable predicate device, either through your own evaluation or assessment, or through FDA feedback, and you believe the device may be classified into Class I or Class II, per the de novo process. Again, direct de novo is characterizing this. So in this case, the first step is that you submit your de novo application. In this application, you would provide the evidence that establishes reasonable assurance of safety and effectiveness of the new device.

This will typically include information submitted in the traditional 510(k) submission, such as the device description, the labeling, and performance testing, which may be bench, animal and/or clinical evidence, and then you go through the classification information in which you would characterize the risk to health associated with the new device, characterize how risk may be mitigated, providing the rationale for why the device does not fit into an existing regulation, either 510(k) or PMA, and again, if you propose a Class II classification, then identifying special controls to mitigate the risk to health.

Step two is that FDA reviews the application and again, we either grant the de novo or decline it. This elaborate flow chart is included in the draft guidance, the 2014 draft de novo guidance, and it illustrates the new proposed pathway for the de novo. I referred to it earlier, getting feedback from the FDA. This is a very important slide. I encourage you to take into consideration that we strongly encourage that you use the pre-submission program if you have a de novo candidate.

Importantly, it would be appropriate to use this after you finalize and establish your device design and intended use. The reason for this is that both of those factors may influence whether or not your product is de novo eligible. In addition, it would be strongly encouraged to meet after your submission information has been collected regarding the safety and effectiveness of your device, because you will better establish a test method for your product.

Again, if you have a novel device with no FDA regulatory history, based on your research, again, this is a good de novo candidate. This is a good reason to have a pre-submission meeting with the FDA to get some feedback. The pre-submission program guidance is referred to here in this link.

So after the de novo process, what happens after a de novo is granted? Well several things occur. So first, the new device is now legally marketed. It's subject to all of the appropriate post-market requirements that are applicable to that device and class, including general controls and special controls if they were enacted and applicable to that device. In addition, that new device will establish a new classification regulation. That new device is then eligible to serve as a predicate for future similar devices, which would then follow the standard 510(k) process.

FDA does several things, as well. First, we will publish an order that announces the new classification and controls, and in addition, we will generate a decision summary that is publicly available.

Now, for those familiar with PMA, this is somewhat similar to the summary of safety and effectiveness data that is available after a PMA is approved.

Here I'm showing a screen of one of our websites, which would be very useful for you to consider in doing your research. This is found on FDA’s transparency website and the home page of the De novo summary that are housed. Here is the link to that page, that home page.

Now here if we drill down further, we can see here we've listed device names, the file number and in this third column, we have the classification order, which is the official decision for FDA granting a de novo, and in the right column, the decision summary. This is FDA's explanation for the de novo that was granted.

Here I have some examples. So here is page one and three of a sample classification order, and as you can see, here we list new the regulation number. We also list the new regulation name and the regulation class. Here is Class II.  On the bottom left, we also have a description of the new device. On page three, we have the discussion regarding the risk and how risks were mitigated. You will see this for every de novo that is granted and in the order itself.

Here is a sample of the first two pages of the FDA decision summary. This follows a somewhat standard template in which we describe the device that we reviewed, the indications and intended use that was proposed and granted, and then we go into the detail of the review of the evidence and the classification decision made. These are great resources if you are looking at the candidate de novo and wish to look for some examples of de novos that have been granted and what was accepted by the FDA. It’s a great resource.

Starting in August of 2014, we established the de novo database. Here is the screen shot for that. And here we listed all the de novos that have been granted since the beginning of the program in 1997. The left column here is the device name. The second column here to the left is a requester. Then we have the two columns in the middle - the de novo number, which I'll get to in a second, and the 510(k) number. Note that some of these 510(k) numbers are blank, and I will explain that in a second. Finally here, you have the decision date. This is a comprehensive listing of all de novos that have been granted since the beginning of the program.

This is a relatively new database started in August. It’s a wonderful resource. Here is a link to that database.

Let's discuss this now. For de novos, we have the submission identification unique ID. Here is the example. The first three letters are DEN, which refers to de novo.

The next two characters are going to be two numbers, and this will be the year of the submission. So for 2014, those numbers will be 14. The last four characters that are noted by z, are numbers, and these will be the submission increment from 0001, upward. Now it is important to know this naming structure was effective with new submissions, as of August 2014.

So for 510(k)s that lead to a de novo, they'll have both a 510(k) number and a DEN number. For direct de novos, they won't have a 510(k) number. As I showed in that prior slide, there were some de novos that had only the DEN number and no 510(k). Those are direct de novos. So that will be the clue to you that there was no 510(k) before.

Now we went retrospectively for all de novos granted, and so we've gone through, again, the history of the program and retroactively assigned DEN IDs to the prior de novos. They will also stay in the 510(k) numbers they were included with.

So now let's switch gears and talk about the suggested information that would be recommended for inclusion in your de novo application. The caveat here is that the content you will see in the next few slides is directly pulled from the 2014 draft guidance. The disclaimer for draft guidances is that it is not to be implemented at this time. However, the information, especially for this information, may be useful for consideration and inclusion in your submission. While it is not required or officially for implementation, it has a lot of useful information that you should consider in inclusion of your de novo application.

Let's go through this in some detail. So the first section is the information that informs who you are and how we contact you. You would include your applicant name, contact name, your address and information such as your phone, fax and e-mail.

Next, in the De novo, it is recommended to include the regulatory history. Now this would be the regulatory history that you had with FDA on this same device. It is possible you had prior a 510(k) and a related NSE decision, or potentially clinical evidence was collected under an IDE. You may have also had a pre-submission or a pre-sub with the FDA on this, or possibly, this was a previously withdrawn or declined de novo. So if this applies to you, any of these items, it would be very useful and important to describe this within your de novo application. It helps provide the context of what we're talking about.

Next, we get into the device itself. Here you describe your device, provide a device description, very clearly state the intended use or indications for use statement, describe the device in terms of its technological characteristics and the labeling.

Next, this is where we talk about the classification summary. This is very important for you in step four. This is where you will have done your research to inform FDA of how you believe that your device is truly a new device, and what that means is, through your review of FDA classifications and existing regulations, as well as approved PMAs, this is your way of indicating that you believe this is a new device that FDA has not previously classified.

Again, this is going back to section 513 (f)(1) of the FD&C Act. Again, this is a very important section, so if your device was approved under a PMA or previously cleared under a 510(k), you're not eligible for the de novo.

In step five, once you’ve established in your submission that you believe you're truly a unique device, you then inform us how you believe we should regulate this. So you provide a recommended classification, either Class I or Class II. The device could be exempt or nonexempt, again your recommendation.

And finally, your justification for the recommended classification, the controls, and if you propose it be exempt, your explanation of why it should be an exempt advice. If you are proposing your new device be classified into Class II, we'd also ask that you identify the proposed special controls with which your device would comply.

In Section seven, this is where you would provide your evidence, your safety and effectiveness evidence that supports your product. So with this evidence, this includes the methods, data and results of your product. The testing may include pre-clinical evidence, or it may also include animal evidence, clinical testing, whatever is warranted to support the safety and effectiveness of your new device. You would correlate the evidence that you collected with the recommended classification for your device and control.

Now this slide talks about the actual spirit of the classification and characterization of the risk and mitigation of these risks. So this is part of the de novo process where you're trying to justify why the device may be appropriately reclassified into Class I or two, and you're able to characterize the risks. So the three sections describe that.

In section 11, we go into the benefit risk considerations. This is your opportunity to describe how the benefits with the recommended general and special controls outweigh the risk of the device for the class that you identify.

Section 12 is the device labeling, which complies with section 201(m) of the FD&C Act.

So now that we've gone through the de novo submission content, let's switch gears and discuss what are some of the best practices and helpful hints that will help you facilitate the de novo process and lead to good quality submission? The first thing is - do your homework - specifically, do your homework with the regulatory research to show that your new device is truly eligible for a de novo. Again, this is where you would verify that your new device is not already classified by FDA. If we have already classified your device, it’s not eligible for the de novo program. Research everything and all available databases, including 510(k), PMA and classification databases, as well as the de novo database in order to fully understand FDA’s prior decisions on devices we’ve classified.

This is very important step and a helpful hint if you pursue direct de novo, and especially if you don't obtain FDA feedback prior to doing so.

The next helpful hint, be specific with and finalize the device description and intended use of your new device. This is very important because these key components will inform whether or not the new device has a legitimate predicate to which it may be compared. If you change this from over time then it is important to know the predicate device that you established and whether or not it will land on the de novo pathway.

The third helpful hint - complete all the required performance testing prior to submission of the de novo. Your de novo application should be your best effort to include all of the comprehensive and necessary information for FDA to make the final de novo decision. Again, this would be all of your evidence, which may include bench, animal in vivo, in vitro, and/ or clinical evidence.

Each de novo will need the level of testing to characterize the level of risk of the device, to demonstrate reasonable assurance of safety and effectiveness of the device, and the appropriateness of the controls that you cited. Now it’s important to note that clinical evidence may not always be required for a de novo submission, but it’s likely in many cases.

The fourth helpful hint - ensure that the data do support the proposed intended use. If you propose an intended use for multiple patient populations, for example, provide evidence for all of those groups. If you only provide evidence for one of the patient populations, then we'd expect you to provide a justification for why you did not directly test those other patient subgroups.

Correlate each risk to health with a mitigation. To do this, it is recommended you consider similarities of a new device risk with mitigation use for other devices. This is where we’re looking at precedent we’ve established with other de novos may be helpful. Look at special controls granted for other de novos.

This is going to the database, looking at other de novo orders, as well as our FDA summaries of de novos. These are all great resources for you to consider. Take advantage of them.

You should address each risk to health with at least one mitigation. Now being low risk helps support the eligibility for de novo, but that isn't enough to be granted a de novo. It is very likely that a low risk device will be more likely to be considered de novo, but you still have to be able to characterize the risk to health and provide reproducible controls to manage those risks.

So as we recap, you’re probably thinking about this presentation and may be left with the overarching question - does my device qualify for de novo? Let's walk through that.

The first is, has the device type already been classified by FDA? Now by device type, this again, couples both the intended use and the technological characteristics of your new device throughout the 510(k) pathway. We'd ask, is there an applicable predicate device? Through the PMA pathway, we would ask, has the device type been approved under a PMA? If the answer is yes, then you are not eligible for a de novo.

The next is the factors to consider for the new device. Does the device present low risk or moderate risk? Can we identify the risk to health associated with the new device? Can we identify the necessary controls - general and/or special - to mitigate those risks? If you answer yes to each of the questions, then there is a good chance you may be eligible for the de novo program.

So let's recap. The de novo program provides means for a new medical device to get to market. Next, the eligibility for a de novo is based on several factors, such as FDA precedent, level of risk and the ability to characterize and mitigate risks of the device. Third, the information needed in a de novo includes evidence that both demonstrate the safety and effectiveness of a new device, as well as the ability to classify the device and the device type. And finally, there are several key resources, such as the FDA Pre-submission Program and public domain information on our website that may be useful for you as you're pursuing a de novo.

The FDA provides industry education in the form of several different ways. The first is through CDRH Learn, a multi-media industry education platform, where we have over 80 modules of videos, audio recordings and power point presentations that are available to you. We also have Device Advice, a text-based educational resource with a wide range of pages that provide comprehensive regulatory information on pre-market and post-market topics. I have links for both of these resources on the slide. And finally, the third and perhaps the most significant, is our division itself, the Division of Industry and Consumer Education.

If you have a question, you can e-mail us at the address listed on the slide or contact us by phone. Our home page on the web is listed on the link. Thanks for watching.