Initiating Pre-Market Clinical Investigations in the EU: What You Need to Know

Hello, and welcome, everyone, to today's session, Initiating Pre-Market Clinical Studies in the EU, What You Need to Know. I'm Sean Smith with MedTech Leading Voice, and I am absolutely thrilled to have with me today Daniela Cara, and Matteo Mosa from Donowa Life Science. Daniela, did I say it right? Close enough?

More or less, more or less.

More or less. Okay. So, the reason I'm so excited today is because we're kicking off our first, 5-day email mini-course, which, is the companion course that goes along with this, the 5 Biggest Mistakes Sponsors Make and How to Avoid Them. Each day, you'll receive a 2-3 minute lesson directly in your inbox. You can unsubscribe at any time. But what I'd like you to do right now is if, if, Is to check your email and your spam folder, and let me know if you've received… just give me a thumbs up if you've received a zero message in your inbox already. And if you haven't checked your junk mail folder, or if you don't see it, then write, I didn't get it in…

the chat, okay? This session will be recorded, and the slides and the replay will be available tomorrow. You'll get them approximately 24 hours afterwards. I'm gonna copy-paste in the registration for the 5-day course. Which I encourage you to share with your colleagues. Why not? share it with them. Certificates of attendance, will be provided if you'd like one. You should put your name and email address in the chat. As you would like it to appear on the certificate of attendance and an email for us to send it to. Give us a day or two to get those done, we do them by hand. For questions, please submit your questions using the QA function as opposed to the chat function.

Otherwise, I have to switch back and forth between the two, and that's not fun for me. The, last thing is that there will be a short poll about 20 minutes into the call, and it'll be followed by a survey afterward. If you have any questions, please, put them in the chat for me, and I am going to turn it over to Daniela and Matteo. Thank you.

Yep. Good afternoon, good morning, everybody. I'll start. Sharing my screen… Yep. Yeah, okay. So, welcome, everybody! In the, first slide, I wanted to show… oops… Yeah. But I will start with the story, the story on where real life beats fiction, and I thought of this because that's… that gives an input of, why… what… what are the reasons between, behind the idea of, running this webinar.

So, this is the story. A while ago, a US company comes to us and asks for help for rescuing a study. The study was a pre-market study, so exactly, the key topic of this webinar. Today, it was planned in two, European countries. One of them involved us. High-risk cardiovascular implantable, device. When they contacted us, they had activated 11 sites. And all sites had been activated 4 months prior to, the, contact with us.

And they had zero patients implanted. And, to the big surprise was that not only that, which was enough of a problem. They had spent 30% of the budget for monitoring. I wasn't certain whether I should say this, because it seems that it's a fake story, but it is not, really. It's real life. So, we were engaged by them, and we reassessed all sites, and eventually 4 of them were closed. A number of motivational visits were done to the sites, and enrollment took off, the study was completed, and the device was CMARC.

Couple of years later. So… So this summarizes a bit what we're gonna touch on today, what are the issues when initiating a clinical study, pre-market clinical study. Okay, trying to go, down, it doesn't switch… okay. So, this is the agenda for today. We'll touch on the regulatory framework. We have to do it with regulatory, sorry. I've learned this a while ago, we cannot do without it. So, just an overview. And then, a very important topic. Partner selection, selection of investigators and clinical sites.

Then we'll talk about the regulatory submission pathway and some budget considerations with mistakes that we often see. And then some notes about what happens, what is peculiar to Europe after the first patient is, enrolled, after first patient in? So, starting with, sorry, I'm moving my thing. So, landing in Europe for the first time, I realized that… so, we are a complex, continent, languages, 27 countries, and 24 languages. It is complex. But we are a quite big market.

We have nearly, half a billion, people living here. So, a lot of opportunities, and we have achieved quite a substantial harmonization in regulations for the med tech world. I say substantial, it's not entire harmonization, so you're gonna see, a few, times that we've mentioned country-specific, country-specific, so there are indeed some country-specific Elements to keep in mind, but overall, the framework for clinical studies is harmonized.

Actually, I realized after having prepared this slide that this… this seems to refer, and it does refer, actually, to foreign companies that maybe have never landed to Europe. But we believe that some of the elements of this webinar will be helpful to companies that are well-established in Europe, but they never conducted a pre-market study in Europe, according to the current regulatory framework. So certainly, there are gonna be some tips for them as well. So, these are the kind of six pillars for pre-market studies. On top, we have the medical device regulation that I've mentioned, MDR, from now on.

going clockwise, we have the harmonized Standard ISO for 10155, that includes the good clinical practices for medical device studies. We'll touch on that later. Then we have a set of, regularly updated documents, MDCG, which stands for Medical Device Coordination Group. Guidance documents, they can be found online. Then we have the General Data Protection Regulation in Europe, that is the short name is the GDPR. the GDPR… Sorry, I don't know if you see the black… bar, the bottom of my screen, do you see that? Because I see it.

And it hides… no, okay, perfect, sorry. So, GDPR is the regulation that in Europe covers data protection for any kind of processing of personal data. So, it's not specific to clinical research, but it does impact Clinical research, heavily. And then, counterclockwise, Helsinki Declaration, I think that most of you, if not all, are familiar with that. Principles of biomedical research, And what I anticipated earlier, some country-specific regulations.

Oh. Sorry, I'm trying to change slides, and it doesn't. Okay. Sorry. Okay, this is the MDR. I'm sure that many of you are familiar with that. We will simply call it from now on. MDR, it's an extremely long document. It covers a lot more than clinical investigations. It covers all the cycle… the life cycle of medical devices in Europe. And it's been effective since 2021, so it's not new. Okay, I have to apologize now, because we have 3 slides with lists. I don't like lists, but that was unavoidable. So, I thought it was useful for everyone just to have an idea of what the MDR articles, include, and the topics that they have.

So, the key elements for clinical investigations are in Chapter 6, Article 61-22, Annex 1, there's something that's very important is Annex 15. What do they cover? So, 61's clinical evaluation. So it covers whether you should not do, or whether you have to do a clinical study in order to achieve conformity or not, so it's very critical. It's… Slightly outside the focus of today's webinar, because we are assuming that you're planning a clinical study here. a pre-market clinical study. Article 62, general requirements. It touches on legal representatives, study design, investigator qualifications, and others.

63 is the informed consent, and it's… it details the content of the informed consent and the process. Very useful. You don't need much more than that in order to draft. A compliant, informed consent for your study. Then we have four articles that cover studies involving vulnerable subjects. So, incapacitated subjects, minors, pregnant women, or subjects in emergency situations. Again, they will be relevant and very useful in case the Your study, touches is, involves these, populations.

Insurance, Article 69. 1771, it details the process through which competent authority review and assess applications for clinical investigations. So the timelines, etc. And I'll give more details later. Then we have Article 62, 72, 73, 77. It touches on EUDAMED. EUMED is the electronic system that will include several, details of clinical studies when it becomes

active. So there are certain modules that are already active and working, not so for clinical investigations. And, so for the time being, this will be in place in the foreseeable future, but we do not know exactly when. So, for now, UDAMed is out of questions. Then it touches amendments, and… End of study reporting. 7879, Coordinated Assessment Procedure. What is that? So, in the, again, foreseeable future, multi-country studies in Europe We'll need to submit their protocols not to every competent authority in each country, as it is currently, but we'll be able to select one

Competent authority of the participating states, and it will be fine to have approval for one member states only. The bad… this is the good news. The bad news is that this is not yet in place, it's in… it's in a pilot phase now, currently, and it will be mandatory from May 2027. Last slide with the list. But very important. It's Article 80, Reporting of Adverse Events. This is very, peculiar. For Europe, it's different from what happens, for example, in the US. US have clearly different requirements.

And given the importance of adverse events and expedited reporting of serious… of certain serious adverse events and device deficiencies, this is a very important article. Our next one, device labels, instructions for use and packaging. for, pre-market studies, and then on next 15. That's the core. Last one, but maybe, maybe first one to read. Which are the documents to be, submitted to the competent authority, and above all, detailed itemized contents, required contents of study protocols and of the investigator brochure. And other sponsor obligations.

Okay, so for those of you that are not familiar with this document, if you're planning to run a pre-market study in Europe, but even a post-market one, honestly. We warmly suggest to buy it, should be bought on the ISOARC. website, which… Now, maybe it's showing… So it's clinical investigation for medical devices, it's good clinical practices. Now, this document covers all study phases. It's the sister-brother, how you want to call it, of ICH, GCPs. They have very big similarities, and quite…

quite a few but important differences. So, ICH TCPs are not the same as ISO 14155. It's an FDA-recognized standard, so if you're planning a study in Europe and the US, that's Perfect document to use. as a reference. And again, we will cover here just initiation of studies, but this document covers all phases, from the planning, to the conduct, to the end. And covers the responsibilities of the various actors in the process that are sponsor, investigators, ethics committees, etc.

So it's a very useful document for planning, and for drafting your SOPs, if you need to, or for updating them. And it does have very useful annexes, so it's not the typically regulatory burden type of document. It's very useful. It's being amended, so look for the update, 2025. It's, gonna be… should be out quite soon. Okay, these are just… just a brief mention of the other pillars, for the regulatory, so the Helsinki Declaration, it's always to be kept in mind. GDPR, we touched on it.

The MDCG guidance, now they're divided by topic, so there's a dedicated topic on clinical investigations. 21 I checked the other day, and there are 21, guidance documents, issued currently. Clearly, they're always, evolving, so… so check… check on that. I have to say that not all of them are so useful or necessary. Sometimes they're kind of repeating what it's already contained in other documents, the MDR or ISO, but sometimes they are, because MDR does not give sufficient guidance. And then we have country-specific regulations.

Which adds some burden, but the good thing is that they mainly affect the submission process and the sequence, the logistics, and maybe some additional documents that some countries ask for. So once that the study starts, there's a big harmonization. It's the end of the country-specific regulations. Okay? I'm trying to be reassuring. So, snapshot summary, what to… what to keep in mind. So, something that is quite often forgotten is that foreign companies without a legal place of business in Europe will need to appoint two

representatives can even be covered by the same institution or service company. So the legal representative, it's Article 62 of the MDR, and the GDPR representative, so a local representative for all matters related to data protection. Don't forget, because that's gonna be required by the competent authority. They're gonna ask for the names and the address. Study documents, compliance with what we've said, MDR, Chapter 6, Annex 1, 15, GDPR, and country-specific regulations. Well, ethics committees, they refer to national law, okay? So the core set of documents is established at European level.

Ethics committees will work on a national level basis. And clearly, local language is indeed required for certain documents. The informed consent for sure, but quite often the synopsis, and potentially the instructions for use. You need approval by two institutions in each country, that's the competent authority and an ethics committee. You'll need to have site agreements signed before enrollment can start. And then, don't forget about clinical SOPs, developed or updated, because they are indeed checked, and we are exactly in these days seeing that with an inspection, that it's

Happening in one of the countries that we deal with, namely Denmark. And they are gonna check out clinical SOPs from the sponsor. Okay! So I'll, I'll let Matteo talk about… Very important topic, maybe the most important. So I'll stop sharing.

Okay, thank you, Daniela, for your introductory part. So, let me share my screen as well. Alright. Okay… Here we go. Okay So, hello everybody, thank you for joining this webinar. I will be presenting a brief overview on site selection And I hope that the information that I will be providing will be somehow useful for you in the future, should you decide to start a clinical investigation in Europe, either

It's a pre-market, or… post-market, I mean, general concepts are more or less similar, but, I mean, at the moment, we are focusing on pre-market clinical investigations. So… When you come to Europe for the study, the first question that we receive is, which country? Where do I go? So this is the main question that we receive, and we believe that, honestly, this is not the best approach to start selecting investigators. So, unless you have a specific reason for choosing a specific country, the main focus and the main objective should be finding investigators, which would be good investigators. And to do that, you should have

a very robust and reliable procedure to go through the selection. Why is that? Because, investigators are the key element for… the two main, reasons for having a study successful. So, first, enrollment, and second is data quality. So, those are the two main elements that will drive your study to success. I wish to start by telling you some, case studies that really happened to us. Which drove the study into a true nightmare. So, the first case was, in a proof-of-concept study.

So, pilot study, where we had an investigator that was supposed to be a close friend of the medical director of the company. So, strongly suggested, who, at the beginning, enrolled quite steadily, so they, they went through a good pace of enrollment, but when it came to monitoring, we realized that more than 30% of the data were missing. And that there was, an internal fight between study coordinators and investigators. on who was responsible for what, and nobody was doing nothing. Bottom, bottom line is that, at the end, we had to…

Avoid data cleaning because of so many gaps, and have database lock with, with plenty of missing data. So this is one example of an investigator who was chosen by the sponsor. Another interesting case that has just recently happened to us is for a pivotal study. Where, we had, an investigator who was strongly supported by the marketing department of the company. And, so, site selection was poorly done, and out of the 10 patients that he was supposed to enroll, he only enrolled 1.

And, when he started to enter the data, he realized that this was too much work, too cumbersome, and he refused to continue entering the data at the point that we were forced to hire a dedicated study coordinator, so extra money for the sponsor. And and even at the end, he refused to keep the investigator file at his location, so the sponsor had to find a dedicated, warehouse where to store, long-term the study documentation of that site. And similarly, another site for the same study in another country,

In this case, the enrollment was not too bad, but we discovered during monitoring that the source documentation was so poor that source data verification was almost impossible there, and we had to exclude Half of the patients from the database because of missing supporting documentation. So, as you can see, these stories are… Things that really happen, and that you would never wish to occur in one of your studies. So, what to do? Choosing good investigators, of course, will provide several benefits. So, as we have already discussed, enrollment is the first one, and data quality is the second. But there are also other aspects that are, still,

similarly important. So, a good site will use appropriately the device, and This will enhance subject safety. There are chances that the study will start early, and also the protocol will be followed carefully. And all of these aspects will translate at the end in having Budget, consistent with what is, what was planned, since the beginning. So where to start, for selecting, the investigator? So… Of course, the first starting point, I think, is the internet, the…

The web is a great source of information, so you can consult for, public databases, such as clinicaltrials.gov, to see if there are, similar studies. You can search, also, public databases for publications, there are also, the professional societies that can be supportive in providing information of investigators, or you can meet in-person people during Congress. or, or, and so on. Let's say that the key aspect here is that

For a successful study, and for a successful, identification of sites and investigators. A good starting point would be to have and identify a coordinating investigator who could be a true ambassador of your study. By promoting it among the community of other investigators, so… When this happens, other investigators that are contacted by your ambassador will be, normally more motivated to run the study, so… I, we believe that this is a good, a good approach, where to start.

So, differences between Pilot studies, which are normally smaller in size, have a smaller sample size, require less, less patience. And, a limited number of sites. first of all, because for a… for a pilot study, you should try to limit all the variables, so usually two, three sites is a good option. We strongly suggest not to go with only one site. This is because, of course, if that site site fails, then the entire study will, will be, will crash. And…

As in those kind of studies, timelines are more compressed. We believe that it is very important to have investigators who have sufficient time to run the study and really be interested. In the, in the project, so this normally guarantees, good results. We often have seen that selection of key opinion leaders has been strongly supported by sponsors, but in the end, this is not always the best choice. We had, another recent, case study where in a pilot study in cardiology, where we have, a… an implantable device, Class III implantable device.

That the… the… the principal investigators, he's, felt that he was so… expert in the matter that the protocol was… was not adequate, and he thought, well, to enroll patients by, deliberately violating inclusion criteria that he found to be not relevant. So, this somehow demonstrates that… Key opinion leaders is not always, the best options to go. On the other hand, if we speak about, pivotal studies where numbers are larger. In this case, of course, the enrollment is the key element, so the capacity of the site to provide the number of patients that are required for the study, and to have a dedicated team that is reliable and that can support

the conduction of the study. Keep in mind that you should, in these cases where, you know, numbers are large, take into consideration that some sites may may fail, or may have problems. In that case, it's a very good, let's say, decision to, add some backup investigators who can act as, exactly as a backup in case others fail. And, when we move to larger studies, there is always the possibility that the marketing, is keen in providing and suggesting names. So, sometimes that could be fine, but, In our experience, we have observed that most of the situations normally bring to a bad experience in that case. I'm not saying that you should not take into account

Marketing suggestions, but if that's the case, carefully assess the site to make sure that he… the team and the site will perform as expected. So… why, why so many issues in, in, in clinic, I mean, in site selection and, in studies? This is because, normally, this activity is, really under, considered, poorly by, by most of the sponsors. They, normally tend to save money in this kind of activity. And, as normally, now, there is, technology is, is helping us in, you know, doing remote visits,

we, we have seen more and more, sponsors, going with the site selection, by assessing the site through remote pre-study visits, which we believe is, is not the best, is not the best options. And, during the discussion, most of the times when you are discussing with key opinion leaders, we have seen that, you know, promises are, are accepted, rather than assessing carefully the facts. Normally, as a rule of thumb, we, divide by two what what are the promises from an investigator. He says that he can enroll 10, we normally…

consider that 5 would be more or less the, the reality. And, as I said, so, you know, searching for big names, is not, is, is sometimes, not, not the best, not the best to, to go. And, Another important aspect is relative to the fact that many sponsors tend to do site selection by themselves. Which is fine from a certain point of view, but having an independent opinion of professionals of the field, we believe, can provide a value for a proper site selection.

So… what are the main aspects that we believe can promote, can help companies in selecting good investigators? First of all, will depend, of course, from the degree of innovation of your device. This will raise investigators' interest. But also, you can attract investigators by proposing involvement in the project at a more broader level. So, if you're starting with a pilot, you may present What are your future plans for, pivotal studies, and try to engage and to involve, investigators also in the, let's say in the planning and in the development of the protocol.

Another aspect that we feel is, is… somehow important, because we have seen, pretty often in, clinical studies with medical devices that budgets are, Quite low, especially if you compare them with studies, with, study drugs. Pharma companies may have, you know, a bigger budget, but, even if the… even if money is not always the number one factor, we believe that proposing a fair budget surely helps. And last but not least is the possibility to have, you know, publications, though this can be somehow of interest in some of the investigators.

So, how to move forward? We strongly suggest to perform formal pre-study visits, So follow the standard, and, try to document in writing, all the assessment. critical is having in-person visits, as we have discussed previously. This is the best way to verify if the organization at the site is, is working properly, and what is the number of ongoing studies,

at the moment, at, at each site. This is, particularly important for. key opinion leaders, where we know that in some circumstances, they are more keen in accepting new studies just to have a bigger number to show to their colleagues, so… take good care of assessing those aspects. And be very clear on what are the expectations regarding enrollment. As we said, normally they tend to promise exceptional enrollment, while at the end, the reality is very, very different. And,

And one of the aspects that we feel to, I mean, emphasize is really make sure that the protocol is read carefully. Normally, you just rely on receiving the protocol signature page as a demonstration that the protocol was read, which is not always the case. Honestly, we have seen So many, sites that, at the site initiation, when, the CRA is presenting the inclusion-exclusion criteria. Investigators jump and say, but with this criteria, half of our population is excluded. So, this is, one of the important aspects that I think should be really taken care of.

And, as previously mentioned, I think that involving independent professionals brings added value to having an impartial evaluation of the site. So, last comment, take-home message is, that we strongly recommend to invest time and money for the site selection, so you will Spend more at the beginning, but this, at the end, brings value, and in the long term, you will save time and money, and you probably will have higher chances of success in the study.

And, yeah, this was my last slide.

So while we're transitioning, I'm gonna go ahead and start the poll question. If you would kindly take a moment to… complete the poll. It should be appearing on your screen. And, while that's gonna run for about a minute and a half, two minutes. Well, you have a chance to answer the questions. Where are we going next? Daniela, are we back to you? I think you're muted.

S.

There we go.

Okay, here we go. Right. Submission pathway, what to do? I just checked quickly the questions. This is not Article 82 nor 74, for those familiar, this is just a procedure for conformity assessment, studies that are done for conformity assessment, and that includes pilot studies. According to Article 62, okay? So, two submissions, at least… Ethics Committee review, it's needed, and that's based on national law, competent authorities established by the MDR. The blue box reminds you what I mentioned earlier, that the, coordinated assessment procedure is not yet in place. So.

The process between ethics and competent authority can be parallel or sequential, that's really specific for each country. If it's parallel, usually it includes submission into an e-portal of documents. Most often. So the authorities will talk to each other. You just submit everything, and they will coordinate between themselves. That's the ideal thing, and that's usually faster. In other countries, it's sequential, so you submit to the ethics first, obtain approval, and then submit a whole package, including ethics committee approval, to the competent authority. Note that there may be, based on studies and type of studies and countries, additional

Approvals that may be needed at site level. This is a list of documents required per MDR Annex 15. It's the core set of documents for the Competent Authority submission. we start from this one, because that's, at European level, and that's common to all countries. Some countries are gonna add some country-specific requirements. And once that you have this document set up, it will be easier, because some of them will be requested also by the Ethics Committee. So quickly, clinical investigation plan is the study protocol.

They renamed it, but it's the study protocol, the SIP. Investigator's brochure. informed consent, this summary of the benefit risk analysis. Note that, per MDR, only summary is needed, but there are some competent authority that request the whole Risk analysis document. Instructions for use on sample labels, declaration of conformity. with the GSPRs in Annex 1, Clinical evaluation plan. Don't forget about it, this is needed. You see approval? I said ethics committee approval, it's required unless the submission happens in one single shot.

Insurance certificate and the names of the two representatives that we've mentioned earlier. Legal representative and GDPR representative. Country-specific documents, what are they? Well, I posted here some examples. For example, France, for this type of studies, they also request the PMCF, that stands for Post-market clinical follow-up plan. Italy, they ask for site qualification form, that show site suitability to participate in that study. And they need to be signed by the head of each participating site, according to certain requirements which are specific for Italy.

And more and more countries are asking GCP certificate for investigators. And sometimes, in Germany, they even ask specifically what the GCP course should be. It's not any GCP course, okay? Must have a minimum number of hours, so it's quite detailed. Okay… I'm sorry, I'm trying to… okay. So, Ethics Committee submission, it's most of the documents requested by the competent authority, not all. And in addition, they will focus on site agreements. In most cases, they ask either for the draft of the site agreements. Or, budget details about study-specific procedures compared to standard of care procedures. This may be requested by the Ethics Committee or by the administrative department to finalize site agreements.

And then other… Other documents as well. This is a representation of the timelines for the competent authority submission and the review and approval of the studies. taken, from the MDR. Now, the… outside of the details, the key things to note are two. One is that there are two phases. One is the validation phase. It's the first one. They check that the package is complete, and there are no major… Gaps compared to what is needed. Otherwise, they come back to you, and the diagram shows the timelines for each response, okay?

Once the validation is passed, they tell you clearly, and from that moment on, you enter the assessment phase. Now, What is important is that for lower classes of devices, according to the MDR, So Class 1 non-invasive, Class 2A and 2B devices, once the validation phase has passed, and you have obtained an Ethics Committee approval. Enrollment can start, meaning that the competent authority will go on with the assessment and may come back to you at a later time point. In which case, you're gonna need to deal with that.

But enrollment can start. earlier. In the case of higher-risk devices, after the validation phase, you need to wait for the assessment phase to be completed, so to have full approval by the competent authority and the ethics committee. Overall, what are the timelines? Ethics Committee, 30, 60 days, plus… Exchange time with the sponsor, competent authority. 7 125 days, plus, again, the time with exchanging. The key elements here are the time for exchanging with the sponsor. So, the delaying factor here

In addition to, luck, because that's always present. It's also the quality of document that you submit, how accurate the documents were drafted, not only formal, I'm talking of the content, and now the regulations were respected. So, what must be avoided is the ping-pong with the authorities. Especially if this is on substantial matters. They will come back to you, maybe asking minor things, but that's easy to answer. Maybe there's a signatory missing, or date is wrong, or they wanna… some additional documents, but that's gonna be quite easy to fix. So, all together, we estimate between 3 to 5 months.

in each country. If no major issues arise. Okay, and that's clearly… this is an inevitable difference, because there are simple studies, even if it's a first in men or a pre-market study, and there are very high-risk studies, and this is why retirements vary. Don't forget that you may need Not only… you… you actually will need These two, plus site agreement signed, plus Any additional approval that may be required at site level. A few tips on site agreements.

So… the… the thing… several countries, more and more, they have national templates. You should stick to those templates. Don't try to change them. That's our recommendation. It's… it's, sometimes they are really templates that you cannot change, sometimes they are preferred templates. In both cases, we will only recommend that you… Wimp your… whip, sorry. your legal advisor and ask them to be ready and to be fast in their review, rather than expecting that clinical sites do that for you on your changes, etc.

Start the process early, practically in parallel. So the question should be, which documents do I need to submit for the ethics committee? Competent authority, okay. And what is the process for site agreements? Okay. Budget considerations… Some notes. We have compared recent figures, and we've seen that, for example, compared to the US, investigators' fees are roughly 1.52-fold lower than in the US. And that's the same for, CROs. Based on our experience, the things that should be avoided, really study delay, because it impacts everything.

It delays market access. So, no one in your company is gonna be happy. CEO, the marketing team, no one. that's for market access, but even, cost for the clinical study will go up. Number of countries, yes, they do impact study cost more than sites. So… Unless you have a reason for choosing multiple countries. And remembering what, Matteo said, that the focus should be on sites. So, if you have a very good… 3 good sites in 3 different countries, go for it. I'm not saying that you should not do it because it's gonna cost more, because you… what you spend more in submission costs.

You know, different countries. and having a local CRA, etc, it's gonna be recuperated with data quality and enrollment, okay? So… The other issues are with data quality and missing data. Missing data, data that are collected but are not put in the CRF, for example, or protocol deviations, informed consent that are not signed. Major protocol deviations, Serious things. Another thing is major protocol amendments. Sometimes that's not really avoidable, because the design of the product is ongoing while you're planning your study.

But do your best to avoid that, because a major protocol amendment means a chain of changes throughout virtually all study documents with cost raising. Okay, common pitfalls. Budget. Site selection, I think that the message went through strong. Spend money, they're long-term partners, and key to success. Submission cost is definitely not the main budget driver. Multiple zeros for different countries can be a good idea, but you need to have in-house, very strong project management skills. and SOPs, and control.

Fixed-price contracts driving zero selection. We think that this is a mistake, because when projects change, and that's the first, mentioned that I've done when motivational visits were charged to the client, such as monitoring visits, where there was no patient being monitored. So, be careful with that. Large EDC systems for small studies, or with less than 100 patients, they are unjustified. And marketing people, they're very good in selling, but they will disappear once the operations start. There is no reason for using, you know, a Ferrari to buy milk, but I'm quoting this thing that we say in Italy.

Last slide, remember, after first patient team, vigilance reporting. requirements, Article 80, and there's one MDCG documents. You will monitor, collect data, clean, and these are normal GCP-driven activities. Remote monitoring, it's not always allowed. Access to electronic source data as more and more common in the US, is almost impossible in Europe. But remote monitoring through webcams, through alternative methods, is how… can be possible to be checked. Site invoices, you should think that they're often delayed, not raised automatically.

And you need to draft two documents at the end, as a minimum. Final study report with all the results, and public summary for lay users. Public means that they will… that it will become public once the UDAMet is… is in place. And that's the end of it.

Amazing.

We have 30 seconds. Four questions.

Okay, well, we'll try to follow up with the, with the people on answers to their questions, by email. Thank you, everyone, for your time today. Please complete the survey at the end, if you will. help us understand. Again, if you have not received Day Zero of the Thing, please send me an email, or a message, or… smoke signal, or LinkedIn message, or something like that, and we'll try to make sure that you get it. You know, spam filters are really, a problem, but, we hope that you get the 5-day email course, and, you know, persistence is key. I'd like to thank our speakers, Daniela and Mateo, for a wonderful job today. Thank you so much.

Thank you to everybody who lent their time, and I hope to see you all on November the 7th. For, heh. Jeez, I can't remember the name of it. It's, mapping E-Star to 62304. I don't remember the, the IEC number, but at any rate, that'll be a lot of fun. So, keep your eye out for that, and, everybody have a great week. Thank you.

Bye-bye! Thanks!

Bye!

buddy.

Thank you.

Thank you.