What to know before you 510(k)
From our work with medical device startups and corporate pharma, one of the biggest fears, and most consequential challenges, is getting that all important regulatory approval and permission to market your product in a target region.
Failure here often has big consequences. A re-submission not only delays revenue on the product you've been working long and hard on, but incurs significant extra cost; in time until you're ready to apply again, in resources to re-write applications or gather clinical data, and in senior leader or investor confidence.
Many products simply don't have the time and resources to be able to survive such a rejection. Meaning years of work lost, and patients ultimately unable to get the advanced care they need.
What does this mean for 510(k)s?
One of the most common regulatory pathways pursued by manufacturers of medical devices and combination products is the US's 510(k). The popularity of this route is twofold:
It gains them access to the US healthcare market, with enormous revenue potential due to its large size and high reimbursement levels
It's perceived as one of the more straightforward routes to approval against other regulatory regimes across the world
But the 510(k) is not always as easy as it seems. Yes it is a different regulatory approach, and is designed with the intention of minimising the regulatory effort needed for lower risk medical devices. But different does not mean simpler, and success requires understanding what the 510(k) is for, the expectations associated with it, and what the FDA need to see to prevent you from receiving a potentially business-ending rejection.
So what does the 510(k) need?
One of the things that health authorities tend to be good at, and this is certainly true of the FDA, is that they published both the rules to be followed to achieve approval, and guidance on how to interpret and apply these rules. In this case, the FDA have a longstanding guidance on what is needed for a 510(k) approval which can be found here.
To understand the 510(k), it's first useful to understand how it differs from the two other routes to device approval in the US - the De Novo, and the Pre-Market Authorisation (PMA).
In all cases, when approving any medical device, the focus is on establishing that it is safe and effective for patients within the scope of its Intended Use - what it is claimed the device achieves clinically, and who it achieves it for. Based on the Intended Use the FDA categorise devices into one of three categories, with Class I the least risky, and Class III the most. The risk class of the device drives the level of evidence that that FDA want to see to sufficiently demonstrate safety and efficacy.
Figure 1 shows what this means for the different approval routes within the US market. The highest risk devices, Class III, nearly always (with some specific exceptions) require explicit demonstration of their safety and efficacy. This is the PMA route, focused on a deep review of the device and associated clinical evidence, and so being relatively more time consuming and costly vs. other routes.
Figure 1: FDA Approval routes based on existence of predicate device and overall risk
Of course, it's not only the highest risk devices that need explicit demonstration of their safety and efficacy. Where a new, innovative, first in class Class I or Class II device seeks approval, this is also the case. While the lower risk means that the depth of review need not be the same as for high risk Class III devices, these novel devices still must be assessed standalone. This is the focus of the De Novo pathway, relatively faster and less expensive than a PMA, but still requiring a lot of detail and assessment.
All of which bring us to the third pathway, the 510(k). The decision made here by the FDA is that, in cases where the device to be approved is similar enough to a device that has already been approved, its safety and efficacy need not be established standalone, but can instead be assessed in comparison to that pre-existing device.
This changes the focus of the 510(k) submission vs. a De Novo or PMA. Rather than aiming to demonstrate the safety and efficacy of the performance form the ground up, it is sufficient to demonstrate that the device is Substantially Equivalent to the already approved - Predicate - system, and so the safety and efficacy profile can be assumed to be the same. This is intended as a lower, but still robust, burden of proof leading to faster and less costly approvals where such a predicate device already exists. These differences are again highlighted more clearly in Figure 1.
A 510(k) is different, but not automatically easier
So far so simple, can we then assume that 510(k)s are always the easier and faster route? Well not quite...for the right device, with the right evidence, yes, but only if we can demonstrate Substantial Equivalence to a clear Predicate Device. Doing so has two elements:
Demonstration that the device to be approved has the same Intended Use as the Predicate Device.
Demonstration that the device to be approved has i) the same Technological Characteristics as the Predicate Device, or ii) has different Technological Characteristics but the information submitted established that the device is as safe and effective as the Predicate Device and does not raise different questions of safety and efficacy than the Predicate Device.
The flowchart provided by the FDA in their written guidance (see Figure 2) highlights this mindset, outlining the key questions they ask to establish points 1 and 2 above.
The 510(k) decision making flowchart
And this is where things can get difficult. While this option can be hugely beneficial in the right situation, it is all to easy, in our enthusiasm for a fast route and efficient route to approval, to convince ourselves that our Intended Use is more similar, or our Technological Characteristics more equivalent than they truly are. This is the point where a 510(k) submission can hit serious problems, of the type that can threaten the success of our product, or even our business overall.
To succeed in a 510(k) then, the key is to understand the expectations that the FDA have around demonstrating Substantial Equivalence, and that we provide the evidence for the similarity of Intended Use, and Technological Characteristics that enable establishment of safety and efficacy and a positive approval decision.
Which raises three key questions:
How do we identify a suitable Predicate Device?
How do we establish we have the same Intended Use?
How do we establish we have the same Technological Characteristics or safety and efficacy profile?
1: Finding our Predicate Device
This is the simplest step to perform, as the FDA maintain a database of legally marketed device, alongside their 3-digit product code here. Before this, however, we must identify the predicate device itself. This is, ultimately, based on our own judgement, in terms of matching the Intended Use of our device to that of an already approved device. This process is helped by the FDA's use of product codes - which gather together devices with the same intended use into categories represented by a this unique 3-digit code - and a Product Code Classification Database which aids searching based on the key details of our device.
2: Establishing the same Intended Use
The FDA outline the key criteria for two devices to be considered as having the same Intended Use, with these criteria also helpful to our initial identification of a Predicate Device in Step 1.
We would recommend, again, looking at the FDA's guidance for a detailed breakdown, with examples, of the factors they consider as leading to the same or differing intended uses.
In general, however, the Intended Use of a device consists of both its Medical Purpose and the target disease and patient population it is intended to be applied to (Indications for Use). It is, then:
Something we establish during the design and development of our device
For which we gather the necessary pre-clinical and clinical data to justify, and
Document in our Instructions for Use, Labeling Claims, and other marketing materials.
The first stage in establishing equivalence of Intended Use, then, is to gather the needed evidence to support the relevant medical purpose and indications for use, and ensure our Instructions for Use, Labeling and marketing materials consistently reflect this
Helpfully here, the FDA publish within their guidance a list of examples describing what factors they consider may cause the Intended Use of two devices to differ. Broadly, the FDA considers the Intended Use of two devices to differ when either:
The medical purpose is different
There is a difference in the Indications for Use that raise a safety or efficacy issue that was not raised by the Predicate Device
There is a difference in the Indications for Use that have the potential to significantly increase a safety or efficacy concern raised by the Predicate Device
Examples of changes that may lead to this include:
A change from a functional/performance indication to a treatment or aesthetic indication
A change from a diagnostic indication to a screening indication, or vice versa
A change in the anatomical structure of use
A change in the patient population (e.g., adult versus pediatric; different disease populations)
A change in the clinical context or setting (e.g., periodic monitoring versus continuous monitoring; hospital versus home use)
What becomes clear is that the criteria by which equivalence, or not, of Intended Use is established are relatively "soft" - meaning here defined at a high level and with an element of subjectivity.
This is another challenging element of a 510(k) submission, which is that it is on us as manufacturers to either justify, with a strong scientific underpinning, that there are no significant changes, or that the changes have no significant impact on safety and efficacy. The success of the submission relies on the strength of the case we can make, scientifically, and so our key task in preparing for our submission is to ensure our positioning is established, accurate, and well-justified.
3: Demonstrating the same Technological Characteristics or Safety and Efficacy Profile
The basis for establishing that our device has the same Technological Characteristics or Safety and Efficacy Profile as our Predicate is similar to that by which we establish the same Intended Use. The key technological characteristics of both devices need to be documented and compared, with justifications made as to why they are equivalent, or not. Where the Technological Characteristics are not equivalent, we must make a case for no changes in the safety and efficacy profile to achieved a determination of Substantial Equivalence.
Again, here, the FDA publish within their guidance a list of factors that may lead to a determination that two devices are not identical in Technological Characteristics, these include differences in:
Function/Performance
Materials used
Energy sources
Software/Hardware features
Density
Porosity
Degradation characteristics
Nature of reagents
Principle of assay method (e.g. for diagnostics)
etc.
Where an individual Technological Characteristic cannot be justified as being equivalent, then the case needs to be made that such differences do not result in different questions of safety and efficacy.
Again, what becomes clear is that the criteria by which the equivalence, or not, of the Technology Characteristics/Safety and Efficacy Profile is established are "soft", and include an element of subjectivity. The key to success, once again, is to justify, with a strong scientific underpinning, that there are no significant changes, or that the changes have no significant impact on safety and efficacy.
To do this, we need to ensure that the data provided to establish this stands up to the scrutiny that will be applied to it (in Stages 5a and 5b of the FDA's process flowchart - see Figure 2). In call cases where we provide data to justify substantial equivalence, we must also be able to demonstrate and justify that the scientific methods use to establish Substantial Equivalence are appropriately robust/acceptable, and that the data itself demonstrates each of the key aspects that make up a Substantial Equivalence determination.
Summary
Where does this all leave us? In summary, a 510(k) submission can be a faster and more effective route to US approval where we are able to justify, using appropriate scientific methods, that our device:
Has the same Intended Use as the Predicate Device.
Has either i) the same Technological Characteristics as the Predicate Device, or ii) has different Technological Characteristics but the information submitted established that the device is as safe and effective as the Predicate Device and does not raise different questions of safety and efficacy.
In doing so, we have to assess carefully the data we are generating, how we are collecting it, and how we are using it to build a case for Substantial Equivalence. While the FDA provide some helpful guidance in this area, ultimately the onus is on us to make sure any submission is accurate, robust, and well-justified scientifically.
It's therefore worth getting all the advice and guidance that we can to make sure we have a watertight submission - by reviewing guidance documents, seeking advice from experts, looking at previous approvals, and entering early dialogue with the FDA to better understand their needs and expectations. Because the consequences of not doing this can be huge: rejected approvals, costly remediation, and perhaps even the overall failure of our product or business.
Are you seeking help or advice in developing your 510(k) submission? Please do contact us directly here for a no obligation 1-on-1 chat