One of the topics discussed during the Medical Device Clinical Trial Seminar in Taipei, was the current medical device clinical trial environment in Europe and how that is evolving. A short version of my presentation, you can find on SlideShare using the following link:
In brief, there are a few key aspects that need to be taken into account when involved in the development and execution of clinical studies with medical devices in Europe, and starting with some of the
What is new in Rev 4 of MEDDEV 2.7/1 are the definitions of clinical data, and especially clinical use, i.e. meaning use of a medical device in a living human subject, including devices without direct contact with a patient. In other words this includes a machine that ensures a continuous fluid flow rate to help raising the temperature of a body cavity.
Also new is the clarification of what is sufficient clinical evidence, i.e. data that are adequate in amount as well as quality: During a clinical evaluation the evaluator needs to take into account sample size as well as the type of trials and the regulations that were followed when the data were collected.
The state of the art is also a newly introduced term, and is relevant when evaluating or designing (a) clinical stud(y)ies as that will tell you what therapy to compare the new treatment with.
Further key definitions concern the ISO 14155 definition of a clinical investigation:
any systematic investigation in one or more human subjects, undertaken to assess the safety or performance of a medical device
which to me means that any trial on safety or performance is included regardless whether it is pre or post-market. The difference being that a pre-market study is a study conducted with non-CE marked devices, or CE marked devices used outside the intended use, and a post-market study a study after CE mark and with the device used according to the IFU, and a PMCF study a post-market study looking to answer specific questions on safety or performance.
Clinical evidence gaps
Under Rev 4 of the MEDDEV 2.7/1 there are 2 scenarios where the clinical evaluation may indicate you have a gap in your clinical evidence and a clinical study is needed:
- When there is insufficient qualitative data to verify that the device meets ER’s 1,3,and 6, and you need a classic Clinical Investigation, or
- when there are unanswered questions regarding safety and performance, for example on long-term performance, and you need a Post Market Clinical Follow-Up Study.
MEDDEV 2.7/1 Rev 4 indicates a pre-market Clinical Investigation is needed when your data are insufficient in quantity (it even has a table with an indication on required numbers for safety) and/ or the data have not been collected in a methodological and scientifically sound manner and/ or in compliance with standards, such as ISO 14155, and it is stressed that incompliant studies should not be used for demonstration of safety and/ or performance of the device. Typically a pre-market study is indicated to be required for implantable and high risk devices, but also for new technologies AND class I and II devices with clinical evidence gaps.
MEDDEV 2.12-2 specifies that a PMCF study generally is required for high risk devices and in case of rare diseases (for the latter the amount of clinical data is often low), but also when patient follow-up in the pre-market study/ ies is not in line with the expected product life time, think implantables such as vaginal meshes for example, or when the CE mark was based on equivalence.
EU Clinical Study Regulatory environment
As mentioned also in previous posts, the regulatory environment for clinical studies in Europe is complex and changing. Some of the directives have already been mentioned above, but at a European level we are currently dealing with MDD, the Declaration of Helsinki, ISO 14155, the different MEDDEV’s, and the different local regulations. The variations in the latter, especially for post-market studies, can make it hard to ensure international studies are run in compliance with the applicable regulations.
The upcoming MDR will make a difference in that respect, as that concerns a regulation to be implemented 1:1 in the local law, it pays much more attention to clinical investigations (count of the word investigation shows a 5-fold increase!), and it requires basically all clinical studies to follow ISO 14155. And mind you, the MDR specifies that also clinical studies not performed as part of the clinical evaluation shall comply with the general basics of good clinical practice’s, so not just the pre-market and post-market clinical investigations.
Study document requirements
So what is generally speaking needed when you are planning to do a clinical study?
Although different in the details and depending on whether it concerns a pre-market of post-market, interventional or observational study, the basics are always the same.
One always needs a protocol, an Informed Consent (also for registries!), regulatory approvals (EC and CA as applicable), a final report, and AE reporting.
Differences between pre- and post-market studies can include for example the need for an Investigator’s Brochure or an IFU, SAE or U(S)ADE expedited reporting, and the need for a study or a liability insurance for a pre-market study or a post-market observational study respectively. From experience I know, however, that the variations are disappearing, and Ethics Committee’s more and more have similar requirements for a pre- and post-market studies regardless whether the latter are observational or not.
Study endpoints and design
Due to variations in medical devices, their intended use, mode of action, and users, designing the right medical device clinical study requires a tailor-made approach for each product:
Measuring safety or undesirable side effects, concerns a relatively clear endpoint as that is all about the collection of Adverse Events, the type, number, severity, and duration. The main item that typically leads to discussion, concerns the sample size; In other words what defines safe, or to what degree are certain device related events acceptable? The table in MEDDEV 2.7/1 provides some guidance in that respect, but typically the focus is to try and capture the serious device related adverse events, so those that relate to the use of the device and led to an injury that is life-threatening, resulted in permanent damage to the body, or required an intervention to prevent this from happening.
The performance endpoint varies a lot with the device involved. Key is that the device must achieve the performances as intended or claimed by the manufacturer, which translates to different study endpoints for a pacemaker, hyperthermic perfusion system, and a dialyzer: The data on the pacemaker for example may have to show that it adequately monitors the heart rate and effectively stimulates the heart when needed, whereas the data of the hyperthermic perfusion system may only need to show that it regulates the rinsing fluid temperature within certain margins.
The effect on the patient also being more clear for one treatment than the other, because performance is not always the same as efficacy: This is where the patient benefit comes into the picture since
benefits are about a positive impact on clinical outcomes, such as a reduced probability of mortality, morbidity, and enhanced Quality of Life, and if anything is claimed by the manufacturer in this respect, clinical data is needed to substantiate the claim.
And then there is the device effect duration to consider: how long do you need to follow a patient before deciding the device is performing as intended? The last in my blog post series regarding clinical evidence dilemma’s will also address this, but the hyperthermic perfusion system and the dialyses can focus on sessions ranging from 2-4 hours, whereas a pacemaker is supposed to perform for 8-10 years! By the time you have collected the clinical data on the pacemaker, the device(model) will be outdated, so typically you extrapolate data or use long-term data from comparable products, and under the current MEDDEV 2.7/1 you will need to do a PMCF study to confirm long-term safety and performance.
Due to the variety in medical devices, the above examples only give an indication of the elements that need to be considered when developing a medical device study and the challenges that come with it, and then I have not addressed design aspects like when you need a RCT or when a single arm study might suffice.
Aspects for consideration when determining the study design include:
Gaps: Is there a gap in your clinical evidence and what is that? Do you need a study comparing your devices performance versus the State of the Art, then a RCT will be needed, a study confirming long-term device performance can be set-up as a single arm observational study.
Standards: before designing a clinical study, one should verify whether there are any other than the general standards you need to comply with and whether that dictates a certain design. In case of IOL’s for example there is the ISO 11979 that describes pretty much when to do, what type of clinical study, including the sample size.
Scope: Are you planning to use the data for device registration elsewhere? The FDA for example indicates to accept OUS clinical data for medical device applications, but is looking for effectiveness data rather than performance. So in case you are considering using the data collected in Europe to support your product approval in the US, you better take that into account.
Summarizing, in Europe there is a clear trend towards higher clinical evidence demands: Clinical definitions are more comprehensive, clinical evaluations require more and better substantiation throughout the medical device life cycle, and the regulatory environment is becoming more strict including any type of clinical study. Since clinical trials are an expensive, time absorbing, but also a responsible activity, their planning, development, and execution should be done with even more care than before.
Please feel free reaching out in case you want to discuss the above or need any support for your medical device study.