December 10, 2019 | Real world evidence—national registries, physician-initiated studies, electronic health records, and physician surveys—has an important role to play in pre- and post-market clinical validation studies, says Jennifer Bolton, Senior Fellow, Regulatory Affairs, Boston Scientific Corporation. But the regulatory environment matters as well.

On behalf of Clinical Research News, Kaitlin Searfoss Kelleher recently spoke to Bolton about validating medical devices and the upcoming European regulations.

Editor’s Note: Kaitlin Searfoss Kelleher, Conference Producer at Cambridge Healthtech Institute, is planning a conference dedicated to Medical Device Clinical Trial Operations and Regulations at the upcoming SCOPE Summit in Orlando, February 18-21. Bolton will be speaking on the program; their conversation has been edited for length and clarity.

Clinical Research News: The medical device industry relies on pre- and post-market studies for clinical validation. Can you tell us a little bit about the different types of studies and why each type might be used?

Jennifer Bolton: Pre-market studies tend to be used primarily in order to support submissions for approval to market the device. Sometimes we also conduct continued access studies here in the US, which are intended to allow the clinical investigators to continue using the device to treat their patients while a product is undergoing a PMA review. These studies often start enrolling after a pivotal study has completed enrollment and entered the follow-up stage. Both of these types of pre-market studies are well controlled with very specific inclusion and exclusion criteria.

Post-marketing studies, on the other hand, are primarily intended to study a device under real world conditions. If the post-approval study is a condition of approval for a PMA, it may also contain a cohort of patients with inclusion/exclusion criteria similar to that used in the pre-market studies, along with an all-comers cohort. Even if not a condition of approval, the post-market study is a way for the sponsor to collect additional clinical data on the device, perhaps to gather more information regarding how the device works in a particular patient population or subpopulation.  Post-market studies are often conducted in multiple countries, not just in the US.

How does real world evidence come into play? What challenges surround getting accurate data and properly analyzing it?

There are multiple sources of real-world experience that the industry can use to gather more information on our devices. Some examples are national registries, physician-initiated studies, electronic health records, and physician surveys. I know many companies are currently looking at ways to gather and analyze data from EHRs, the electronic health records, and/or physician surveys to document real world evidence, especially for clinical evidence being gathered to comply with the new European Medical Device Regulation (EU MDR).

My personal experience has been primarily in using national registries and physician-initiated studies. These are excellent sources of information useful for both pre- and post-market purposes. The challenges mostly come from not being the sponsor. Everything depends on what your contract states with the owner of the data source. For example, it's common that you're only able to obtain de-identified data sets and may not know which site a given patient is from, thus you’re not able to reach out to a site to request additional information regarding an adverse event or in a case where the data provided is incomplete.

Depending upon the contract, you may not be allowed to audit sites, either. You then need to clarify to any regulatory agency you're submitting the real-world evidence to regarding whether you had access to audit sites, what information you were or were not allowed to audit, etc.  In most cases, this will be the same level that a regulatory agency will have access to audit, as well. If you're submitting real world evidence to FDA for example, they will be very interested in this information being defined in your submission because it affects how they might be able to conduct any Bioresearch Monitoring (BIMO) audits for sites where they intend to conduct an audit prior to approving your submission.

You just talked a little bit about regulatory agencies. How do forthcoming regulations out of the EU come into play? Will they change how pre and post-market studies are conducted?

The EU Medical Device Regulation (EU MDR) requires clinical evidence for nearly all classifications of devices. While in the past, many lower classification devices and accessory devices only had preclinical data to support them, now actual clinical evidence or clinical studies are also required. Companies are scrambling now to obtain clinical evidence for these devices. In many cases, these are also accessory devices like guidewires or catheters that never needed to be the subject of a clinical study, but they're used in procedures that may be part of a clinical study. One option is to collect data on these accessory devices whenever you're running a clinical study for a new device. Another option that many companies are looking at is how to collect the appropriate data via a physician survey to provide sufficient clinical evidence. This is especially useful in some lower classification devices like a suture, for instance. Companies have not historically run clinical studies on sutures, however now clinical data / clinical evidence is required to support CE mark.

On the other hand, most higher risk devices, especially implants historically, have had pre- and post-market studies, so I don't really foresee too many changes to how studies will be conducted for this group of products. However, another area where there will be change is when a company modifies their device to market a next generation version of that product. In many cases, depending on the specific modifications, they may historically have only required preclinical testing and not any new clinical studies. The equivalence arguments allowed for by the EU MDR and MEDDEV 2.71/1 revision 4 regarding clinical evaluation is quite useful for these situations. However while in the past it was sufficient to claim equivalence for both initial CE mark and continued certification, now the equivalence claim will only be useful for initial CE certification, and clinical data on the modified device itself will be expected by the time the device is submitted for a recertification application.

Of course there is a deadline for companies to comply with the new MDR before products are pulled from the market. Do you have any insight into how long it will truly take companies to get up to par with these regulations or any advice or input to these companies on how to streamline that process?

Most companies right now are recertifying all of their products [under the Medical Device Directive] while they are planning for their initial MDR submissions. I think everyone is working very hard to come up to speed. There is a lot that is unknown at this time simply because it's not clear how notified bodies and competent authorities will be interpreting every aspect of the new regulations. At this point, companies are having to put a stake in the sand to determine how they're going to interpret a particular requirement and move forward, and then depending upon what feedback they receive during the review of their initial MDR submissions will determine how they address it in the future.

At this time point, there are many guidance documents yet to be published. Many have recently been published, but they’re still not super clear on exactly how the regulations should be interpreted. All we can do is make a decision on how we are going to interpret it and move forward, but it remains to be seen how accurate we are in interpreting the regulations.