Welcome back to MedTech Compliance Chronicles! In this week’s post we jump into the key processes of securing FDA market clearance for medical devices, including premarket notification (510(k)) submissions, premarket application (PMAs), and the registration of Class I devices. We have finally made it! It is quite a long journey to get to this part of bringing a medical device to market in the United States. The final hurdle that stands in the way are the various pathways for market clearance.
While submissions for regulatory clearance are often thought of with dread and mental pictures of dictionary sized binders holding endless documentation, I hope to show in this post that they are not nearly as difficult or complex as they seem. A lot of those pages that cause fright are usually raw data and analysis, which, while critically important and necessary to include, tend to all fall under one or two sections of the application and make it appear more daunting than it is in actuality. For the most part, there is some general information required of all organizations involved in the manufacture of medical devices as well as a process for device listing required of all devices. Beyond that, there are two high-level pathways, the premarket notification, generally required of class II devices and the premarket application, generally required of class III devices.
General & Class I
Up to this point, it has been possible to do everything in every topic of this blog without necessarily interacting with the FDA. Alas, that is over now. Placing a device, even class I, on the market necessarily involves a degree of interaction with FDA. Regardless of what your device is, there are some general activities and information required to be submitted to FDA by all medical device manufacturers in the United States (coincidentally, even if you make export only devices, i.e. do not intend to sell in the US). In this section we will cover establishment registration and device listing.
The first and foremost requirement before marketing is that you register your establishment with the FDA. This (and pretty much all official submissions to FDA) is done through a pathway called the Electronic Submissions Gateway (ESG). You will need to submit basic contact info (name, address, phone #, website, etc.) for the organization, as well as for the owner(s) and a designated contact person for the FDA (if not the same as the owner). This designated contact person will be responsible for receiving and sending all communications to and from FDA - side note, if a non-owner is listed as the designated contact, FDA specifically calls out that this does not remove any liability from the owners of the organization.
In addition to the establishment registration, you must also list all devices which your organization sells or plans to sell. The information about the devices required to list are the proprietary or brand name and either the product code, for devices for which no premarket notification or application is required (generally class I devices), or the premarket notification or application number that was assigned to the 510(k) or PMA.
Now, if the device you are trying to market is class I, you have made it! Establishment registration and device listing is all that is required of class I devices. Now you just need to make sure you are actually following the regulations in your operations for if and when the FDA shows up for inspection. If, however, you happen to have a higher risk device, you will need to submit an application for the FDA’s review, in order for them to determine the acceptability of your device.
Premarket Notification (510(k))
Premarket notification, or as it is most commonly known a 510(k), is the simpler and quicker of the two premarket submission pathways. The 510(k) is a process based on a concept called substantial equivalence. You can read more detail about substantial equivalence and how medical devices are classified in the USA here. For the application, what you need to know is that the point of a 510(k) application is to have identified a device that is already legally marketed in the US with the same indications for use as your device and then prove that your device is at least as safe and at least as effective as that predicate device. We are going to assume that you have identified a predicate device (if you have not, search your device’s product code on the FDA’s device listing page and look for devices with the same indications for use) and jump right into what is required when submitting a 510(k) for review.
The first thing to note, and this also applies to PMAs, is that your application must contain all of the sections required by FDA. If a particular section is not applicable, you must include it and have a letter in that section explaining and justifying why it is not applicable. As far as the actual submission goes, you will need a cover page that states “510(k) Notification” and the basic device and manufacturer information (brand name, device class, contact info, etc.) and a table of contents. You will need either a 510(k) summary or statement. The summary must contain the submitter’s contact info, a complete description of the device (including technological characteristics, principles of operation and foundational scientific concepts), a similar description of the device for which the manufacturer is claiming substantial equivalence and a statement of the intended use and the diseases/injuries/ailments it is meant to treat/diagnose/compensate for. The summary should also briefly describe the results of any testing performed and data analyzed and conclusions to be drawn from them. A 510(k) statement is a standard statement provided in part 807.93 that the submitter puts in place of the summary and signs, essentially attesting that they will provide FDA with all of the above information when requested to do so. The decision as to whether to go ahead and submit all the information in a summary or provide a statement and let FDA ask individually depends on the degree of proprietary information that would be required in the summary. 510(k) summaries are made publicly available, so the primary reason the FDA offers the statement option is to protect organizations’ intellectual property.
The rest of the 510(k) submission will consist of various statements, the proposed labeling and advertisements and, of course, the raw data, test reports, clinical protocols and reports, etc. that make up the evidence for claiming substantial equivalence. For statements, you will need a statement describing the similarity and or differences of the device compared to other legally marketed devices for the same intended uses, a financial certification or disclosure according to 21 CFR part 54 and a statement that you, the submitter, believes to the best of your knowledge that everything in the application is true, accurate and no facts have been omitted. If clinical data was collected, a statement that good clinical practices were followed according to 21 CFR parts 50 and 56. As far as the test reports and data go, remember that being in class II means that “special controls” have been implemented for that particular type of device. Special controls come in the form of performance standards, which can either be FDA specific standards or recognized consensus standards. The specific types of special controls that apply to a particular device can be found in the device specific regulations 21 CFR parts 862-892. The test reports and data analysis need to provide objective evidence of conformance to these standards.
One final note on 510(k)’s. You may have heard of a ‘special’ or ‘abbreviated’ 510(k), I will briefly describe these here. A special 510(k) is used when a manufacturer is implementing a significant change to their own device but is not changing the intended use or fundamental technological characteristics. An abbreviated 510(k) is mostly the same as a traditional 510(k) described above, except that the submitting organization has had the device tested, usually by 3rd party testing facilities, according to the relevant performance standards. If this has been done, the submitter may just submit the declarations of conformity to the standards and the final test reports in lieu of all the raw data, protocols, etc.
Premarket Application
Finally, the premarket application, reserved for the highest risk, class III devices. Premarket applications are often seen as significantly more burdensome than premarket notifications. However, most of that is, again, in the much larger amount of data or much more complex design characteristics as far as the actual application itself goes, there is not a significant difference. The biggest difference really lies in the fundamental goal of the application. With a 510(k) the goal is to prove that your device is substantially equivalent to a device the FDA has already cleared and has established a standard for. For devices requiring premarket approval, the FDA has inherently not created such standards yet, so the goal of the application is to prove to the FDA that your device is safe and effective.
Similarly to the 510(k) you will need to start with a cover letter providing your contact information and a table of contents, FDA is a little stricter on requiring the table of contents to specify the volume and page number of every item referred to. You must provide a summary for a PMA, containing many of the same things as a 510(k) summary with a few key differences. First, you will not need a comparison to a predicate device, however, you will need a summary of alternative practices and procedures to treat/diagnose the same conditions as your device. You will also need to describe the marketing history of your device, if any, this would include any other countries it is marketed in, if it has had prior clearance in the US and if it's clearance was withdrawn or revoked in any country for any reason. The summary of studies required for PMA is more detailed, generally a full abstract of each individual study is required, touching on the objectives, experimental design and data collection and analysis.
The next section will be the device description, which should include, in addition to the 510(k) requirements, pictorial representations (which are good to include in a 510(k) even though not required), each functional component, the properties of the device relevant to the intended function and the methods of manufacture of the device as well as all associated controls. Another section will then detail the performance or consensus standards complied with and how the device complies with the standard(s) or justify any noncompliance. Note - you may be wondering why a section on performance standards is necessary when the reason most devices require PMAs is that no specific performance standard exists. This is true, for the specific device, however, there may be some more general standards that still do apply to, for example if the device uses electricity, the IEC 60601 series for Medical Electrical equipment likely still applies to it.
The next two sections will be the study reports for all of your clinical and laboratory testing of the device, the two types of studies are required to be in separate sections. For the laboratory testing section, the results and reports of each will suffice. For the clinical investigations, much more information on the design of the study, selection of subjects and subject information is required in addition to the final reports and results. If only one clinical study was performed for the PMA, this will also need to be justified and you must be able to demonstrate that the data from that study is generally applicable to your whole intended patient population. Each study (both laboratory and clinical) shall be accompanied by a statement attesting that the studies were performed according to good laboratory practices and, for clinical studies, that an institutional review board was utilized and human subjects were adequately protected per 21 CFR part 50.
The next section of the PMA will be a bibliography of all published reports regarding the device and an identification of all non-published information relevant to the safety and effectiveness of the device. This is a section of particular importance. You are not just allowed to cherry pick studies that show your device (or similar devices) in good light and ignore negative reports. You must submit all reasonably known information about the device from all sources, whether they be positive or negative. You do not need to include these reports or information in the PMA but should have them all readily available should the FDA request them.
Getting down to the physical components, you will need to provide FDA with all proposed labeling (remember that advertisements can be considered labeling) and also a sample of the device itself. If it is not reasonable to provide a sample of the device itself, you must provide a location where FDA can come and inspect the device at a reasonable time.
Finally, you will need the same financial disclosure and statement of accuracy of information as required by the 510(k). Additionally, you will need an environmental assessment per 21 CFR part 25 and to provide information on expected pediatric use. The information on pediatric use should include identification of the pediatric subpopulations (infant, toddler, etc.) that suffer from the condition and the number of affected pediatric patients. If color additives are used in or on the device you will want to check section 721 of the FD & C act to see if the color additive is subject to that regulation.
That’s it! Except that you must periodically update the FDA as new safety and effectiveness information becomes available. All PMAs must submit a three month follow-up and from there as new information becomes available or as you are requested by FDA. As far as additional types of PMAs, there is the modular PMA and the product development protocol (PDP), which are both similar in that you start contact with FDA earlier in the development cycle and send FDA pieces (modules) of the PMA as they become available. The main difference between modular and PDP is that with PDP you communicate to FDA during design and development and reach a predetermined agreement as to what evidence is needed to prove the safety and effectiveness of the device. With the modular PMA, the design and development have usually been completed without FDA contact as with a traditional PMA but may require lengthy testing or time to develop the manufacturing facilities and so the organization may choose a modular PMA to begin the application process while certain aspects are still ongoing and send updates as the different “modules” of information become available.
Conclusion
The application process for marketing a medical device can feel quite cumbersome. While impossible to completely break down all of the details of each in a single blog post, I hope I have been successful in at least reducing the perceived complexity of the applications. They both ultimately boil down to a detailed summary and a compilation of the evidence that proves either substantial equivalence or safety and effectiveness, along with a couple legal statements. In general, FDA targets 90 days to review a 510 (k) and 180 to review a PMA. In both any time the FDA is waiting on information they have requested from you, that clock will stop. Remember that the number one most important part is that you have a complete application and that your evidence is scientifically valid. If those two things are done, FDA is usually very good at working with applicants to resolve other issues.
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