Post-Market Clinical Studies in Non-Traditional Settings Avoiding Common Pitfalls

Hello, and welcome everybody. Today's webinar on post market. Clinical studies I'm pleased to have with me today 4 excellent speakers, Kathlyn Mazaros from Diane, legere from dn.

B. And BI know.

Sorry. I'm sorry. It's all. Good morning. Daniela Carrera from Dona Life, Science, and Matteo Mosso, also from Dona a couple housekeeping notes before we get started. Just to Let everybody join. and let's see, housekeeping notes are, please use the Q. And a function to submit questions to the speakers. We may not be able to get to all of the questions today, but we will try to follow up with you afterwards with any unanswered questions. Secondly, if you would like a certificate of attendance from today's session. please put your name as you would like it to appear, along with your email address into the chat, not the Q. And a. The chat. Use the chat to request your certificate of attendance.

Next is The recording will be made available to everyone tomorrow, and I believe the slides will as well. Let's see. Oh. tomorrow there is another webinar and then Friday there is the Friday and focus call tomorrow's webinar is okay. Brain isn't working this morning. I'll get back to you later on. What tomorrow's Webinar is. In the meantime I would like to allow each of the speakers to introduce themselves quickly, and then we're going to move to the presentations. Thank you. Everyone for joining.

To tell us who should start.

Diane, why don't you start?

Okay, Hello, everyone. So my background is I'm an advanced practice, critical care. Nurse and I mostly did that in pediatrics, and then worked a little bit of industry, and then into notified body work for about the last 5 years. So I'm a clinical assessor with Dnv. That's really it. Well, there's lots more. But for today.

Kathlyn.

Yeah. Hi, everyone. My name is Dr. Kathleen Mesaros, and I'm a clinical reviewer at Senior medical Expert for dental devices, and I also work on the next 16 aesthetic devices. My clinical background is 12 years working as a general dentist in the Uk. And also obviously with aesthetic devices like Derma fillers. But I'm based in the Uk. This is, in short.

As requested.

Yes.

Hello, everybody! I am Daniela Carter. My role is current role is Vp operations and clinical affairs at science in Italy. My background, I'm in. Biology is by education. I spent several years in basic research and cell biology, then worked in several years in a Cro large Cerro that does not exist anymore. Used to be covens in Pharma trials and then for the last more than 15 years. Here at Donna life science dealing with studies, with medical devices and in vitro diagnostics.

Thank you. And Matteo.

Yes, hello, everyone. I am Matteo Mosso, and I'm director. Clinical affairs here at Donawa. My background is that I am a chemist and have been working in clinical research for the last 26 years, starting 1st with the big Pharma companies, and then in the last 13 years I joined Donna, and have been working on medical devices.

Thank you very much. So let's go ahead and get started. people are still joining. But that's okay. Who's who's presenting first? st

I am presenting. First, st let's see if I can get this working. so I'll share my screen right.

Oh, and tomorrow's Webinar is about Mdsap and I'm, putting the link in.

Okay.

Beautiful.

Can you see my screen right.

Yes.

Okay? Good. So it's a pleasure to start this webinar today that focuses on post market clinical studies in non-traditional settings. I'll explain what we mean by that, and we'll talk about pitfalls that we, as a 0, have often encountered in our in our daily life here. So what is the challenge? And why non-traditional settings have higher, stronger challenges than traditional Pmcf studies? Well. one of the challenges is the signing studies that are really close to the scope that I should have. This may seem quite obvious, but

sometimes we see that that's not the case. We see protocols that are not really purpose built. and they take too much from free market study protocols. They're cloning it with a number of consequences that I'll touch on later on then. the challenge clearly is the challenge for any studies. So avoid delay. Be able to start the study quickly and optimize cost. Don't spend money that you're not supposed to spend and therefore optimize planning. And then the the last bullet point here mentions something which is really crucial is choosing the right partners in your study.

That's even more important and relevant when we talk of non traditional settings, and that part is gonna be covered by Mattel also in the next presentation. So why are we seeing more and more Pmcf studies done in unusual settings? And well, I I took this sentence on the Internet. And it seems that it's quite. There's quite common consensus that between 5 and 10 times increase in Pmcf activities and studies. why, I mean, clearly this is linked to Mdr implementation to enforce the regulatory requirements. We'll hear from the 2 representatives of the notified bodies that we have here today what they can tell us. And the enforcement touches all device classes. And that's the key point.

Some. Sometimes we've been seeing that there are specific data that are missing from the initial submissions that are requested by notified bodies on certain indications and populations. And then we have the group of legacy devices that for which we see gaps in data in clinical data. So they're unable to achieve in the Rc. Marking without running another study. And sometimes the gaps are so big that we see very complex studies. And I'm talking about randomized clinical studies in a post market setting. So it's sort of

chimera between something that should be relatively relatively simple, with the highest complexity. That is the randomized clinical study. what I'm what I've depicted here. It's just with no text. The text comes on the next slide. But basically, what is the shift that we are experiencing? As a Cro. So there are a lot more studies and a lot more unusual signs where we find ourselves to work. So on the left is the the traditional work, I mean. I'm not so young that I've only seen the part on the right. Actually, I've seen most of the times, the part on the left so big hospitals and clinics.

And I mean, this is a surgery room clean. It doesn't need to be that, but it gives you a feel of the environment where the studies were run until most studies were run, and then a very varied and well educated team. So with several medical doctors, sometimes each with their specialty nurses, study coordinators, etc. more and more we see the situations depicted on the right, where the environment is different, the number of people involved is different. The education and the roles of the healthcare professionals is different. Not to mention the home use and wearables, for example, where the data collection environment is patients home.

This is a bit listed here. So we're seeing more and more small private practices being involved. such as Gp offices, physiotherapist offices, sometimes residential homes. So really different types of settings, patients, homes. I've I've touched on that in this condition. Sometimes a physician is not even present on a regular basis. So you, the the people that as a Cro as a study monitor, introducing or explaining the study to a clinical side, you have that most of the people are not physicians. so they had no clue of what the execute declaration is, or Gcps. Etcetera. They have a lot more background in clinical research.

So a lot less. And even the way that they're organized, the tools, the desks, the space that they have. It's limited people and equipment. When I was preparing these slides. I had a number of ideas, and and I realized that some of the pitfalls that we do see for studies in this type of unusual settings are really common to all Pmcf studies. That's that's why I introduced some of pitfalls that we see across all the Dmcf. Studies, not only those in the unusual environments. And I'm touching on the planning phase here.

So this is really crucial. So it's the identification of the population of the study. That is the inclusion, exclusion, criteria. And quite often we see studies that start as observational studies. That's how they call themselves. And then they have inclusion, exclusion, criteria, mirroring just copy and paste prompt distractions for use. This means that patient selection and assignment to the treatment depends on the study which is exactly the opposite of what should happen in an observational study where you just record what happens in real life?

And if this is the I mean, there are situations and type of studies where this is required. But if the study is truly observational treatment with a device. and that goes into the second bullet point here. treatment. Implantation of the device is independent from the study would happen anyway. and that's crucial to clarify that it has a number of consequences of confusion and even financial implications. Okay. something else I want to mention is the off label use. So if investigators are asked to check before they treat the patients that all the instructions for use are expected. That is the inclusion, exclusion, criteria of their study.

This means that by definition they're not including off-label use in their tests. and they are checked by the assigned clinical monitor that they do their work well, right? So you are not gonna gather any information on off label use how it happens in real world. And that's so. There are several consequences to that. 1st of all. as you most of you know, the Ndr is one objective is to exactly to the death of label use. So if the study is observational, this is a mistake, because you're excluding off-label patients, and you're making sure that the investigator does not enroll any off-label patient.

There are other reasons. I'll bring 2 simple example on that. We worked with a company 3, 4 years ago that following the identification of extensive use for their product. So their product was used in an indication that was not part of the sea marking the extent of this phenomenon was so high that they believe that they want to protect their company. So what they did is to include they've included in their I fuse a big warning statement, saying warning, do not use this device for this indication, because it has safety implications.

So they did this to protect themselves. Okay. And I think that this was a very useful thing to do. a second aspect that we've encountered in our 0 life. Is the the fact that off label use may represent a potential new indication for the product. I have an example here of the same product that had to be used together with another device. So they had to be used with another component. Let's say the company detected in one site that this doctor was actually using the device alone, so off-label without the second component.

But they found this interesting. So what they've done. They made up their mind they they are now running, and we are close to the end. Actually a pre-market study for the new indication, because they found it interesting. Okay, so off label use can be important. And I think that I also covered the second point. So there is no screening step. If your study is observational, you talk to a patient that whether or not they participate in the study they will have treatment. Anyway. This is linked to this bullet point here clarify as much as possible standard of care versus study, specific procedures.

And so often this is not present in study protocols. And this impacts investigators fees the money that the company has to pay, not to mention the regulatory process, because there there are gonna be. And we have seen just today. Very long feedback from an Ethics committee just asking that this is specified in the in the protocol and then other elements that would simply make understanding the study design and the and its regulatory classification more complex. So you will start having a ping pong with the authorities of questions and misunderstanding, so

clarify, if the study is with, with or without invasive burdens and procedures, and it will be very useful to to at least say what is your classification of the study? What you believe is the classification of the study with reference to Ndr. Article 82, or 74, one. and then use descriptors of the study. I have to say that this is done quite often, but sometimes it's not clarifying the matter. I still see often the use of term of registry, which, at least in Europe, is not so common. I know it's mentioned in the standard Iso. 14, 1, 5, 5. Still, it creates a lot of confusion.

So now this is common really, trans, across across all types of study. What is more needed for the studies that we've talked earlier, this non-traditional settings. So consider that the science will likely not have any experience in most cases with clinical research. Sometimes very little. Don't assume that they do, and consider heavy training time. Heavy means 2 times, 3 times it starts from the very basics with examples, graphics slides. You know, you are not at the university. We are used to work in sessions where they say, Okay, this would be very interesting. I've heard this

a hundred times. This is primary school. So start from the very basics. since these sites are sometimes smaller. Consider enrollment boosting strategies, such as ads, and social use, which is, may not be required in larger practices. simplified procedures as much as possible. This is all linked to the fact that these sites are not used, and probably don't have actually they never had study coordinator assigned to the work. Make it easy for them as much as reasonably possible. reduce staff burden again. This can be done. But you need to think of this. For example, allow and bring source data into the crf, that's that's 1 example.

In case of home use, make sure that you choose user. Friendly, simple and efficient electronic patient reported outcome. If that's what you're gonna use. Okay, that's my last slide. So summarizing do not copy and paste from pre-market studies. That's a very common mistake. Oops! Sorry I think you're seeing the fall here. Make sure that your own study documents and I'm talking of the informed consent, the study protocol case, report, form, if if necessary, but essentially these 2 documents they specify what is the scope of the study, the regulatory classification, and which procedures are standard of care compared to the study specific because you're supposed to pay

only for the study specific procedures. If there's confusion here, your budget is gonna go up plan ahead for enrollment issues. If they are there. Simplify site work, make it as easy as possible and train train and train. Okay, I've I've.

That was great. I wanted to give the notified body speakers a chance to comment on this. If they if they'd like let's start with Catelyn.

Oh, yes, so from the notified body. Perspective. Indeed, we did see a huge shift from traditional settings to non-traditional settings. So my background is dentistry and aesthetics. So this is where I'm going to pull a few examples. So now we don't see that much of Pmcf. Studies in hospitals, but rather dental clinics, private dental clinics, aesthetic clinics, private dermatology, practices, and in theory this is great, but because this is where the devices are actually used. and it's also good from a real word evidence standpoint, and it makes sense. But the catch is what has been mentioned here already that these sites are not built for research.

so they may not understand good clinical practice, and sometimes there is a lack of infrastructure for the documentation for the monitoring and follow up, and sometimes they don't even understand the burden that comes with the Pmcf. Study for these clinics. So they they do need extra planning, training and support. And if this extra training is not provided to them that can lead to huge financial issues and burden, as well as as headaches. and sometimes even repetition or repeat of the study. I've got an example here coming from. It's a true story that happened for Derma Filler Company. They came up with 2 clinics, a Pmcf. Study aiming for around 100 patients.

and this 100 patient was statistically justified. And then one of the sites completely fell apart for a simple reason, and that being that the staff was not properly trained for collecting consent. and that led at the end of the study, that one, the entire site, had to be excluded, leaving them only with around 60 valid patients, and had to start an entire new Pmcf. Study. And and again, so that was bumps and bumps and delays, tens of thousands of euros and a lot of frustration.

So yeah, so that's this is a real example of the complications of missed training opportunities for the sites.

Diane, do you have anything you'd like to add.

Sure. Just in short, I just wanted to say that devices can be used in very complex areas that are not just the traditional setting, as Daniela showed us. You know, there's varying patient characteristics, novel devices where there's a learning curve and then also evolving practice clinical practice in in all these areas and many devices. In these non traditional sites, because devices take time to show their clinical benefit and risk. You know, going outside of of these larger university centers. If you, as you stated, allows for gathering this data in a in a very important, in a very important way.

Excellent. Shall we move to Matteo's presentation.

I think we can.

Let me share my screen. Alright. oops. Okay, let me see if I manage to make this. Okay.

okay, can you see? Can you see it? Right? Sean?

Yes, perfect.

Okay, good. Good. Thank you so much. So yes, welcome everybody again. So thank you for joining this webinar. I really hope that you will find my presentation somehow interesting. With some useful insights. When it comes to site management, I will be presenting. showing, and describing through events that occurred to us during the course of recent studies that we have performed within the post-market, clinical follow-up setting. And specifically, I will be touching. after a just very brief presentation, which well, mostly has been covered by the other presenter. I will be touching 3 main areas where we found the most difficulties, so which were in site selection

site training. As this was already mentioned, and the issues that we have observed in terms of performance of the sites and during the conclusions I will be describing how we try to face all these issues, and which are the suggestion that we want to present to the audience so just briefly as we were, we are describing the fact that we are most of the post-market clinical studies need to be performed in the facilities where the device is intended to be used, and as it has been already discussed, this does not, I mean big hospitals, big university centers, or big clinics, do not represent

the target. So I will be. I will be showing you which were the the settings that we have been involved with in. In. And and these scenarios that we have faced in the in these studies. So yes, moving to the 1st area. So site selection challenges. Let's see 1st of all, that we need to distinguish 2 different settings. So one is where the device is already available at the site or countries where it is already marketed. And in this case I mean, we can talk about physiotherapy centers, private practices. And there are instances where the device is not yet available. So

And let's say, in this circumstances we will be discussing about the nursing homes. So which were the difficulties in Site selection. So in the 1st case, where the device is not yet available and the situation relative to nursing homes, we found extremely difficult finding contacts. Having someone who replied to our phone calls emails just to mention that we were aiming to select between 3 and 8 sites. And we sent out more than 50 emails or and the we received only 3 replies, 2 of which were saying, We are not interested, and the 3rd one, which initially the 3rd one that responded, Tell me a little bit more than ended up saying, no, we are not interested. So we found really extremely extremely complex.

trying to reach the the right person in the nursing homes. And this is also because, mainly, the the type of contacts that are available in the Internet are commercial contacts. So it was really extremely difficult. And and they don't have clinical research managers or clinical research staff. That understands what you are trying to propose so, and we will see at the end of the presentation how we manage to get through that. On the other hand in case let's say the difficulties that we have faced when it comes to

sites where there is already the presence of the device. And let's say, there is a strong input from the sales team or the marketing division of the sponsor. In most of most circumstances, site, selection and site qualification is performed by the sponsor. So not digging really deeply into the the critical aspects that Sero is aware of. So this we will see along the presentation which which were the the difficulties that this has has brought

so aside of site selection moving to the training challenges. So Daniela has already mentioned part of this of this of the for this aspect. So the the critical elements that we have found to be that you need to particularly take care of is, 1st of all, the lack of Gcp knowledge. So describing or talking about. Principal investigator, sub investigator study coordinator often means nothing to the people you are talking to. You see, you see faces that are lost, completely lost when you try to describe some basic concept also regarding, for example, source documents.

The simple fact that you know corrections need to be performed according to Gcp principles. What do you think that we found during sort of verification that in many circumstances the correction fluid was used to cover the mistakes. So this demonstrates that it is somehow difficult to explain some kind of basic concepts relative to Gcps another important aspect is relative to the use of the ecrf. which is very common to people who already are working in hospitals, and are used to do clinical research. But, as we have seen, the type of settings that are, I mean this kind of non-traditional settings. They have never seen an ecrf. So, for example, simple things like doing corrections in dynamic forms

can create big problems. So just to mention something like, you know, if you select, male or female, and then another page automatically opens, saying, Is it? Is it pregnant or not? If you select female and you do a corrections in the 1st form. This automatically reflects also in the second one, and sometimes this is not understood, and you end up in having the ecrf, which is then messed up. Or another funny thing was relative to edit checks. if you enter a date which is outside of the protocol specified range, you normally get a warning, saying, Are you sure this is the correct date? And some of the investigators were just

changing the date until they found one that did not fire the other check just because they were afraid that the warning was an error message that they were doing something wrong. So, understanding some some of the concepts behind. The use of the tools for a for a study is sometimes very difficult to to explain, and another big problem was relative to making them understand that a study running a study is not the same as doing standard standard practice. So as as Kathleen was also mentioning the fact that some adverse events are not captured because they are

thought to be, you know, standard occurrence, something that is normally happening. So nothing nothing to be different from from the normal practice or following study procedures, such as doing visits at specific time points. sometimes has created big concerns with with the investigators, and so moving ahead to what were the issues relative to site performance. So we have noticed several errors that were done. some of those were relative to the ecrf, as I partially mentioned. But just to give you another example.

we discovered that in 1 1 of the sites where they had to report into the ecrf some basic demographic information of the user of the device. We were observing that along the study they had many changes. So 1st user was 30 years of age and male. Then it was female, 20 years 25 years of age, and so on. And when we asked, How is it possible that you are changing so many times the the user, I mean in the delegation log, we only have one user. Why is this occurring? And the answer was, well, we just don't want to disclose private information of the user which honestly, was surprising for us, and the fact that they don't understand

that. For example, an ecrf is not a public web despite it in the Internet, it's a let's say it's a protected area. So concept relative to the use of the Ecrf created this kind of errors. Other examples relative to compliance with study procedures were the fact that we, we discovered that some investigators were performing treatments additional treatments beyond the beyond the the protocol specified timeframe. That's just because they thought that

the treatments that they did were not sufficiently effective. So creating. I said, big difficulties, or for example, the incorrect use of the device. So in our in our cases, we we had to set the device with certain parameters relative to the patient characteristics, and in certain circumstances they just forgot to update. And so some patients were overtreated and some other patients were undertreated because they forgot to change the the settings of the device, and probably one of the biggest mistakes that the investigators have done was the underestimation of the workload. So, even though we try to

describe and explain which are the duties and the and the difficulties of of running a study. Still, this has, I mean, this was really underestimated, and in certain circumstances we had to renegotiate the study, the the budget, the investigator fees because they realized that the workload so was so much higher compared to what they were thinking at the beginning that they they had to ask for additional compensation. So this is just to give you an idea of the type of problems that can arise. When you have to deal with non-conventional sites.

So, heading along to the conclusions regarding site selections. So the 1st part, which were the solutions that we implemented so to try to go to get through nursing homes, we did an extensive research on Pubmed, who had, so we found, names of key opinion leaders or expert in the field, who had publicated articles with nursing homes, and we ask them to introduce us. So we 1st got in contact with the key Opinion leaders and asked them to introduce us to a nursing home. And this is what actually happened. And you know, you get in contact with the 1st one. Then the 1st one get gets you in contact with the second one, and so on, and so on. So we ended up in holding 5 nursing homes in the study, which was

exactly within the target that we were aiming at. Another suggestion is to do pre-study visits, let's say, possibly on site I know that most of the companies and the sponsors tend to save money. So trying to do remote activities. With this kind of setting we have, I mean with with non-traditional sites. We really do encourage to to do pre-study visits, to assess and to explain. What is the what is the workload? And what does running a clinical study really mean, because this kind of information is really something new for for the investigators.

and again trying to save money proposing small budgets will only cause additional problems, because at the end the sites will realize that the workload is much higher than what is expected, and then you will end up in renegotiating the the investigator fees, and and so you will end up wasting time in, you know, having addendum to the contract, and so on, and and as I said, try to be very clear when you explain the roles, the duties, and which are the expectations when running a clinical study

moving forward. So what did we really learn? And what's what are the suggestion that I want to to discuss? So invest a lot of time in Gcp training the role of the cra with the site is not only to be a controller, but to really collaborate with with site staff making them understand what what I mean. Good cleanup practice are. And what we did also was to provide the so aside of the regular Gcp training that is done during site initiation visit. We also requested the site staff to follow online courses which did have a test at the end to to get a

certification. And there are free online courses that can provide this this thing. So we strongly recommend to do so. Also, considering the type of errors that we have observed. I mean, if you, when you are developing in the monitoring plan, try to not only focus on the let's say, most important key elements, but think out of the box, try to add additional verification steps. Because you you would never know what what type of errors they will with the sites will make and most importantly, is the fact that

being the investigators, not, I mean not knowing what does a really clinical study mean? They are not aware of the consequences, as Kathleen also mentioned the fact that you may end up in excluding part of the of the subject because you had major protocol deviations is a very big problem that I mean needs to be really avoided. And as this last slide just want to let you have the take home message. So when you have to deal with unconventional nontraditional settings, so take nothing for granted. So really think out of the box and expect the unexpected.

Thank you very much.

Thank you.

That was, that was great, Diane, starting with, expect the unexpected, you know. Let's let's talk. Let's talk.

Sure I have a couple of comments. Burden on staff has been mentioned several times, and I that is not necessarily unexpected, but maybe the extent to how much of that burden really is. And I think that's a as a clinician that's near and dear to my heart that we really need to take into consideration when doing any post market activities that involve clinical staff. so that. And then the warning on the dates that you talked about Mateo, where they kept trying to change it until it got to a good place. So I don't know if you would expect that. But when you talked about that that really hit me when I'm reviewing clinical

projects around. Why, you know, Ifus, just aren't that effective in reducing risks that are found because of that human. Just tell me what you want. And yeah, just how those aren't really effective in mitigating risk. That really made me kind of chuckle when you gave that example, I'll just say one other thing that clinical staff often aren't aware of how their input into devices is important, because a lot of them don't understand about reporting device malfunctions and and their part in that, and that might be something for us all to consider as well.

Thank you. Catalan.

I would like to add something that is really applicable rather for legacy devices that we usually see with the introduction of the Mdr. That they do come with data gaps, and for a quick fix they usually try to do a Pmcf. Study. But what we see as a notified body, and I would like to zoom out a little bit now, generally, for the Pmcf. Studies, if they are not integrated well with the clinical evaluation report methodology. So within the Pmcf. Studies the performance and safety endpoints should match with the clinical evaluation report that was defined in the clinical Evaluation report.

and therefore their outcome parameters can be actually used in the clinical evaluation. So manufacturers and Cros also have to take into consideration not only deliver clinical data per se, but that clinical data is useful from the regulatory standpoint of view. Also, I'm going to give you an example here. So for example, if a study for a Derma filler. for the endpoints were presented like investigator satisfaction scores, patient satisfaction scores. But within the clinical evaluation report something totally else is that is not even remotely aligned, being defined, for example, duration, in effect.

in months, or reduction in wrinkle, severity on a validated scale, these 2 are not comparable at all. So in these cases the data is still provided. Money is spent, but it's the study is not going to be presentable within the clinical evaluation. Therefore it's not necessarily useful for the clinical evaluation, and I think it's also important to mention that manufacturers should really communicate the the clinical evaluation report with the cro. Because that's the way they can really ensure. And we had a short discussion with Daniel as well, and she says that sometimes it happens right, sometimes it's not.

Yes, it depends. Sometimes we see ready made designs. It's just go for it. Or what should we do? As a post market. Now, if you receive the second question clearly, we we we should see what was planned and what's in Cr right.

At the end of the day all of this should be coming from the clinical evaluation report. So then, all of these reports and the studies really become like one big big part of the Pmcf. Strategy as well. So the planning starts within the clinical evaluation report.

Absolutely.

So we have another a number of interesting questions. If I may address this one to notified bodies. are you finding that notified body experts are willing to take into consideration a more least burden, least burdensome acceptability of a Pmcf. Study design, understanding the nontraditional site limitations? Or or is there an expectation that sponsors train these non-traditional settings to function as research centers? So first, st I'm gonna you know? I guess the question is, is there any leeway in non-traditional settings, or are they held to the exact same standards as as universities?

I'm gonna stab, and then we can add, add to it. I really don't like it when they use the word lenient. So I struggle, I struggle with with that when when manufacturers ask that question to me, but I'm going to say that for me, for my reviews, when I see studies that are done in in the context of real world use. Usually, we're not looking for is this effective or not? We're usually looking more for non-inferiority. And does this at least meet state of the art, so that in itself changes the the study itself so deeper, contextually appropriate data? Sure, I do. I need a hundred. Maybe I only need a 50 because of. As I said, the the data is contextually rich. So that to me is more the question than

you know looking for for leniency.

What I would like to add is, it also depends what kind of clinical data is already available. because the clinical evidence should be coming from the again from the clinical Evaluation report. And if we see strong clinical evidence with high scientific validity, clinical studies, then the further Pmcf. Study studies doesn't necessarily need to be that high quality be, and then can move to non traditional settings. However, if we already see something lose data being collected from private practices, then, that really leaves us in a in a challenging position whether to accept further

non traditional setting clinical data. So it depends on really what is in the clinical evaluation. I would say that.

Hmm, so the next question is, if there is a minor slash major change. which that's a huge difference on the Pmcf. Design as what the Pmcf plan in the Cr. How do we usually handle it? Should we talk to the notified body 1st for a discussion on the change I would assume? Yes.

Absolutely. Yes, please do contact your notified body. and probably talk to the clinical reviewers or a clinical expert in the field, whether the change that is proposed. I guess in this case it's just proposed change not already. A documented change is still going to be acceptable. I mean, like, it's always worth to have a discussion than rather being picked up during a surveillance audit. And then then you cannot take it back once it's been done. So if you're gonna be. I had these discussions already, and

It absolutely makes sense to.

To discuss with the notified body. First.st

Thank you.

Yeah, or even worse, your certificate application fails if the change does not meet the expectations for sufficient clinical data, right? So there's also that risk. So yes, please talk to us. We're not that bad.

Yeah.

So here's a question, probably from Matteo. But possibly Daniela, regarding to site budget as, per your experience do. Most of the sites expect a full procedure cost to be covered by the sponsor. What is the usually negotiable factor with the site. you know.

It's always a balance, because, of course, sponsors tend to save money as much as possible, and there is the the fact that the those type of sites non traditional settings that are not used to do studies. So they do not know exactly what to ask. So I believe that somehow the I mean the support of a Cro can be beneficial in this circumstances, because we can provide some advice also to and I mean, enter, step in in the discussions. So as we have seen, the risk is that you tend to underpay

the site. So have a lower, a low budget which makes the sponsor happy. But at the end of the story will not. I mean the it's not. It's not a reality, because the the site will realize soon that what they are being paid is not sufficient to cover the workload. So I mean, it's a complex matter when it comes to budget negotiation. My suggestion is, try to be as fair as possible.

Can I add just something? So what's critical is that? It's specified somewhere, and that's often lacking. What is a study procedure? What is a standard of care procedure. So if the studies observational, the sponsor should never pay unless they have reasons for willing to pay, but should never pay for treatment because treatment is done as part of standard of care. And you only collect the data. Okay, so this is critical. And if there's confusion there the risk, and we have seen that is, that the sites would ask for paying for an implantation that they would have done anyway. But since this is part of the clinical study. I'm asking you money.

So yeah, I mean, just just that.

So we have to wrap up. I would like to give each of the speakers 15 seconds to, you know. Say goodbye. Thank everyone. I want to thank all the attendees. I want to remind everybody. Tomorrow the Mdsap webinar is in the link. Please sign up Fridays on the Friday and focus call, and Diane.

Really quickly. Sure. So thank you. Everyone. And I just want to say that remember, post-market activities overall are not add-ons. They're becoming more and more important and getting more and more focused. So everyone needs to sort of get on board with that.

Catalyn.

Yeah, thank you. Everyone for attending. Maybe the most important takeaway from the notified body. Perspective is always align. Your Pmcf. Studies with the clinical evaluation report, and also make sure that you train your staff working at the sites properly.

Matteo.

Yes, thank you. Everyone for joining this, this presentation, this webinar. I really hope that you found it useful, and that you can take home some of the information that we were able to share.

Thank you. And Daniela.

Hi, everybody. Just thank you for attending. I strongly believe that simpler studies can be done with high quality. So it's not a complex study means high quality and simpler study means automatically low quality. The 2 things can go together. I'm optimistic.

I agree.

No, but I am. I am. I am even in data collection and talking to small practices, etc. There is a way through which you can obtain data that have a certain level of reliability.

Thank you. All this has been an enlightening topic. I haven't heard it before, and I want to thank you for joining us, and hope everybody has a good day or good evening.

Thank you. Bye.

Bye, bye.

Bye.

Hi.