Non-binding Guidance: Breakthrough Devices Program

September 12, 2019
15:51 minutes

The sixth installment of Ropes & Gray’s podcast series, Non-binding Guidance, continues our two-part discussion on FDA expedited review programs. In this episode, Ropes & Gray lawyer Kellie Combs interviews her partner Greg Levine, who provides an overview of FDA’s new Breakthrough Devices Program. This program, which was finalized in late 2018, aims to expedite the development and FDA premarket review of devices used in the treatment or diagnosis of serious or life-threatening conditions. The Breakthrough Devices Program provides a variety of benefits to manufacturers, including priority review and more frequent and efficient feedback from FDA during the submission and review process, so that devices receiving breakthrough designation can reach the patients who need them quickly and efficiently. In this episode, Greg dives into the program’s eligibility criteria, benefits, when to apply, and some of the practical considerations associated with the program. Additionally, Kellie and Greg discuss recent trends and developments affecting breakthrough devices and provide examples of devices that have recently received breakthrough device designation or that were approved or cleared as breakthrough devices. Tune in to this discussion to learn more about the program and its impact on the medical device industry.

If you missed last week’s episode on FDA expedited review programs for drugs and biologics, please check it out here.


Kellie Combs: Hi. I'm Kellie Combs, a partner in the life sciences regulatory and compliance practice group at Ropes & Gray, based in our Washington, D.C. office. Welcome to Non-binding Guidance, a podcast series from Ropes & Gray focused on current trends in FDA regulatory law, as well as other important developments affecting the life sciences industry. I'm here today with my partner Greg Levine. Today's podcast will talk about FDA's Breakthrough Devices Program. In addition to providing an overview of the program, Greg will talk about eligibility criteria, benefits, when to apply, and some of the practical considerations associated with the program. Greg, can you start off by providing an overview of the Breakthrough Devices Program?

Greg Levine: Thanks, Kellie. There's just one single program for expedited review of medical devices – it's called the Breakthrough Devices Program, and that applies both to new devices and to device-led combination products. “Device-led” means that the combination product as a whole is subject to FDA pre-market review through one of the device pathways – the 510K, PMA, or De Novo classification pathways. Congress mandated this program in the 21st Century Cures Act; it was passed in 2016. And the specifics of that program were laid out in FDA guidance that the Agency finalized in December of last year, December 2018, so this is a relatively new program. The current program will replace two existing FDA programs – the Expedited Access Pathway, or the EAP, and the Priority Review Program. Unlike the breakthrough program, the EAP had been limited to devices subject to PMA approval. The newer program is broader in that it includes both De Novo and 510K devices as well. If a device had previously received EAP designation but had not yet been approved, FDA has now deemed that device to be a breakthrough device under the current program.

Kellie Combs: Greg, what are the eligibility criteria for the program?

Greg Levine: At a high level, the criteria are similar to the programs that FDA has had in place for a number of years now for expedited review of drug products. These focus on providing patients with timely access to products, to drugs, in that case, for unmet medical needs in serious or life-threatening conditions, but there are a lot of differences in the specifics. For the device program, the overall structure is that there's one over-arching statutory criterion, which is that the device must provide for more effective treatment or diagnosis of a life-threatening disease or irreversibly debilitating human disease or condition. And then the second criterion, which is showing that at least one of four additional factors is met. So I'll go over these individually.

First, as I said, the device must provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions. As FDA has interpreted that statutory language, “more effective” means that there's a reasonable expectation that a device could provide more effective treatment or diagnosis for the disease or condition identified in the applicant's proposed indications for use of the device relative to the current U.S. standard of care. To establish the required reasonable expectation, you need to show that the device can have both technical success and clinical success. A life-threatening disease or condition is one where the likelihood of death is high unless the disease or condition is interrupted, so, for example, an acute stroke or an MI. And an irreversibly debilitating disease or condition is one associated with morbidity that substantially impacts daily functioning, such as certain cancers or ALS.

Now assuming the first criterion can be satisfied, as I mentioned before, you then have to show that you can meet one of four additional criteria, the first being that the device represents a breakthrough technology. This would mean that the device itself is novel technologically or that it represents a novel application of existing technology that has the potential to lead to clinical improvement in diagnosis, treatment, cure, prevention, or mitigation of a life-threatening or irreversibly debilitating disease or condition. So that's one of the four.

Another would be that there's no approved or cleared alternative for the device. This means that there's no alternative drug, biologic, device, or combination product that has received FDA marketing approval after pre-market review or clearance for device for the same indications proposed for the new device. In making that determination, it's irrelevant that there might be an off-label use of a product on the market for that indication or that another product is on the market for that indication but it did not require any pre-market review by FDA. So examples of those types of products would be an exempt device or perhaps an OTC monograph drug.

Alternatively, so this would be the third out of the four, the device could offer significant advantages over existing approved or cleared alternatives. This would apply if there's a potential compared to existing approved or cleared alternatives to reduce or eliminate the need for hospitalization, to improve the quality of life, facilitate patient's ability to manage their own care, or establish longer-term clinical efficacy, for example.

And then lastly, the fourth out of the four possibilities in this prong of the test is that availability is in the best interest of the patient. And obviously that's very broad language that Congress wrote into the statute, but as FDA had interpreted it, this criterion looks at whether the proposed device for the proposed indications would provide some other type of public health benefit not described or addressed by the three other criteria. So, for example, if a device has benefits for patients unable to tolerate available therapy, or if it provides an additional benefit that might improve patient compliance, or addresses a shortage of a particular device, any of those would be examples of these types of other public health benefits.

FDA describes these criteria in detail in the guidance that it put out in December 2018. And one interesting aspect of that guidance is that FDA gives examples of older devices that, had the Breakthrough Device Program existed at the time they were cleared or approved, would have been eligible for the program. And so to provide just two examples of that, FDA says that, for example, a transcatheter heart valve, when that first came on the market, would have been a product where the technology itself would have been considered a breakthrough. Second is, FDA says that a device for earlier diagnosis of pre-eclampsia would be one that offers significant advantages over existing approved or cleared alternatives. I find this guidance to be particularly useful compared to some other FDA guidances as a general matter in that includes a number of specific examples of that nature.

Kellie Combs: Great. Thanks, Greg. And what about the features and benefits of the program?

Greg Levine: First, breakthrough devices automatically qualify for priority review. That's why, as I mentioned earlier, the breakthrough program replaced not only the EAP, the Expedited Access Pathway, but also the Priority Review Program. Second, breakthrough designation generally allows for more frequent and efficient feedback from the FDA during the submission and review process. So in addition to priority review status, an applicant that succeeds in getting breakthrough status can benefit from a number of other expedited procedures that FDA has put in place. One of these FDA is calling “sprint discussions” – that's a new term under the guidance. These are discussions with a goal of reaching mutual agreement between the applicant and FDA on a specific topic within a set time period that the parties agree on. There's no limit on the number of sprint discussions you can have in the course of review for one device, although FDA recommends, and I think common sense dictates, that you would only want to handle one of those at a time. Another would be a Data Development Plan – this is a high-level document to ensure a predicable device assessment and review, and it outlines the data collection expectations for the entire lifecycle of that product. So that would be a document that would be agreed on between the applicant and FDA. Another type of benefit would be a Clinical Protocol Agreement – this would be a written agreement for clinical protocols required for that device to be approved or cleared that would be binding on FDA and the sponsor with certain limited expectations I won't get into here. This is similar to the special protocol assessment that exists for biological products and has been in place for some time in that area. Lastly, in this list of potential benefits, there are more regular status updates or more frequent status updates than otherwise would be the case. So FDA and the sponsor will agree to regular status updates to discuss general progress on the application and next steps or plans for future discussions. The topics, format, and participants for these updates can vary from product to product and application to application. And then lastly, FDA has also committed to expedited manufacturing and quality system reviews for breakthrough devices. This is going to apply, for the most part, to PMA devices. But any device that's subject potentially to a pre-approval inspection could benefit from this aspect of the program.

Kellie Combs: Now that we've talked about eligibility criteria, and features and benefits of the Breakthrough Devices Programs, let's talk about the logistics. So when and how should a sponsor apply for breakthrough designation?

Greg Levine: Most critically is the when piece of that, and a sponsor has to request designation any time before it makes its submission for pre-market review. So if you wait until the time of submission of your application, whether it's a 510K, or a De Novo application, or a PMA, it's too late by that point. As far as the how, sponsors can request designation by submitting a “Designation Request for Breakthrough Device” Q-Submission, what FDA calls a Q-Submission under its pre-submission guidance for medical devices. These submissions for breakthrough devices are not subject to the acceptance review period like most pre-submissions are, so there's not a period of time that FDA has to evaluate whether to accept that submission like it does for most other types of pre-submissions. In such a designation request, you should only include this designation request in the Q-Submission, so it's not a document where you would be covering multiple topics – and that December 2018 guidance has some additional information and a template for making these kind of submissions. It's also important to understand that breakthrough device designation may be granted for multiple devices that have the same proposed intended use – there's no restriction on how many devices can get the designation. But once one device has received approval, clearance, or De Novo authorizing a given indication, the next applicant, the next person that seeks breakthrough designation for that indication, is going to have a higher bar because there's something else on the market for that use.

Kellie Combs: Greg, what happens after you submit your request?

Greg Levine: FDA intends to request additional information within 30 days of receiving such a request and grant or deny the request within 60 days. If a request for breakthrough designation is denied, then the applicant can appeal under the formal appeals process that’s in place for medical devices, which is called the 517A process.

Kellie Combs: Greg, for breakthrough devices, what are some recent developments and trends that we should be aware of?

Greg Levine: One important development to be aware of is that there have been many more applications under this new program, the Breakthrough Devices Program, than there were under the old EAP program. As I mentioned before, that program had been limited to Class III PMA devices. The early signs looked very positive, both in the level of industry interest and in FDA's commitment to making this program work. For example, as of January 2019, FDA had granted 112 breakthrough designation device requests. Examples include devices intended for the treatment of Alzheimer's disease and dementia, oncology applications, opioid abuse, and others. And in 2018, FDA approved or cleared nine devices with breakthrough designations. Just in August of this year, FDA designated five devices for breakthrough designation and approved one other device, so there does seem to be quite a bit of momentum behind this program.

Kellie Combs: Greg, what are some examples of devices that have been recently approved through the program?

Greg Levine: Well, the one that FDA announced most recently on August 16, was a PMA approval for the BAROSTIM NEO system. This is a device intended for improvement of symptoms in patients with advanced heart failure who are not suited for treatment with other heart failure devices, such as cardiac resynchronization therapy. FDA designated this device as a breakthrough product because it treats a life-threatening disease, heart failure, and addresses an unmet medical need because there are patients who can fail to get adequate benefits from the standard treatments and don't have alternative treatment options.

Another product also that was a PMA-approval under the program, and actually was a holdover from the other program – it originally had been designated under the EAP program – was called the Optimizer Smart System. This is a PMA-approved heart failure device, so another cardiac-related device, that uses cardiac contractility modulation to improve heart function. This was the first device in the Breakthrough Devices Program to go before an advisory panel. The advisory panel recommended device approval, despite some concerns about the adequacy of the clinical trial data. And that PMA was approved in March 2019 – and in that case, FDA required a follow-up study as a condition of approval.

And then, lastly, I want to mention one other which was not a PMA device, which is called the Brain Trauma Indicator from Banyan Biomarkers. This was a blood test that detects concussion and is designed to reduce the need for CT scans to detect intracranial lesions. It was authorized for marketing through the De Novo pathway and, according to FDA, De Novo review and Class II designation was completed in less than six months, which is quite an accelerated process. Now, device development for this product was supported by the U.S. Army, so it's possible that that had some influence in FDA in getting them sort of some extra attention, but that's a product that was not a PMA product that was cleared through this program.

Kellie Combs: And finally to close this out, what are the practical considerations to keep in mind with the breakthrough devices program?

Greg Levine: I'd say first and foremost would be to communicate early and often with FDA. As I said before, this is not a program where you can wait until late in the process, or at the time of approval or clearance to apply for. So you'd be wanting to engage in early discussions with the FDA, if possible, to talk about eligibility criteria and apply for designation. Some other things to be aware of, as I mentioned before, if it's a product that would undergo pre-approval and a pre-approval inspection for quality system regulation compliance, you're going to want to make sure that you have your manufacturing process up and running and ready for such an inspection so that you can actually reap the benefits of an accelerated inspection schedule. Similarly would be to anticipate FDA's needs to inspect clinical study sites or to do a sponsor inspection. So again, if you're going to apply and ask for a priority review or a faster review, you're going to want to make sure everything's in order, you've done all your monitoring, and the paperwork's in place to be able to do well in such inspections. And then also to consider the implications for coverage and reimbursement of a product. You know, there's always this tension between getting a product through the FDA quickly and sort of with the least burdensome amount of data that's necessary to get through the FDA, but that may not satisfy requirements for reimbursement of a product, so those are going to have to be balanced out by an applicant.

Kellie Combs: Thanks for tuning into our podcast, Non-binding Guidance, which is brought to you by our attorneys in the life sciences regulatory and compliance practice at Ropes & Gray. For more information about our practice or other topics of interest to life sciences companies, please visit our FDA regulatory practice page at You can also subscribe to Non-binding Guidance and other RopesTalk podcasts in Ropes & Gray's podcast newsroom or on our website by searching for Ropes & Gray podcasts in Apple or on Spotify. Thanks again for listening.

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