EU-CTR: Preparing for trial transition

David Dent:

Very much welcome to Parexel Biotech and to this webinar that we're holding this afternoon on the afternoon of the 24th of November 2023. The subject of this webinar is EU Clinical Trial Regulation 536/2014, and it's a real hands-on experience. So, you're going to get an introduction to our two subject matter experts in a moment, but first of all, on behalf of Parexel Biotech, we very much welcome you to this session and we hope you find it educational.

David Dent:

If we can have the next slide. So, just a little bit of housekeeping. First of all, all of your microphones are muted. We have a lot of people on this webinar, and that's just to help with the background noise. If you want to submit a question, and we very much welcome your questions, please either raise your hand or put your question in the chat. What we will do is we'll address those questions towards the end of the session after our two speakers have finished.

David Dent:

This is to let you know that this webinar is being recorded and we will share a link for this webinar afterwards with you. The webinar will also appear in the public domain, so please be aware of your own confidentiality. When we get to the end of the presentation, we will be stopping the recording so that the question-and-answer session will be held just with these attendees. But please be aware, if you don't wish to identify yourself or your company or your IP, then that's absolutely fine, and during this part of the session that is recorded, then we won't be taking any of those questions. So if you're not happy being recorded, then there is the option, obviously, to leave the meeting, but it's really just the content from our SMEs here that will be recorded. At the end of that and before the Q&A session, we will stop the recording and that will then not be publicly shared.

David Dent:

Next, please. So, my name is David Dent. I'm an Executive Director in Business Development and Head of Market and Business Development for EMEA for Parexel Biotech. I spent 15 years in healthcare in public services, another 15 years in global pharmaceutical industry, and the last seven years within Parexel Biotech within our area of business, obviously clinical research. One of the great benefits of Parexel Biotech is, obviously, we do clinical research services, full service from phase one to phase four. But we also have a very broad and deep expertise in consulting around regulatory matters with a lot of SMEs in the area across all regulatory spheres and across all markets covering, obviously, EMEA, the Americas, Asia Pacific. So, if you have needs that are outside of this particular subject area that we're talking around EU-CTR, then we'd be very happy to talk to you further. At the end of the presentation, there will be some contact details, including an email address and a QR code where you can have and download contact details to get in touch and follow up after this meeting.

David Dent:

So, I am your facilitator for this meeting, and I'm now going to hand over initially to Esther Gil and then to Celina Gonzalez, who are our SMEs that you're going to be hearing from. So, just a little bit about who they are and their background. Esther, please.

Esther Gil:

Thank you, David, for this nice introduction. I am Esther Gil, Senior Director Regulatory Affairs Operations here in Parexel. And pharmacist before joining Parexel, I have been working in the pharmaceutical industry with marketing authorization applications and clinical trial applications. And then, I moved to Parexel 18 years ago. I'm leading the regulatory team in Europe in EMEA region. So, as you may know, we are quite busy with the EU clinical trial regulation right now. Happy to be here today and happy to supporting any question you may have during the seminar. Thank you.

David Dent:

Thank you, Esther. Celina?

Celina Gonzalez-Colaco:

Yes. Thank you, David. So, I am Celina Gonzalez-Colaco, Principal Consultant Regulatory Operation here in Parexel. I joined Parexel two years ago with previous experience of more than 25 years in clinical trial. Last, I have been a clinical trial assessor at the Spanish Agency of Medicine and Medical Devices, and with further experience working at the EMEA in the development of the EU-CTR. I'm very happy to take part in this meeting today and to support in any question that you may have. Thank you.

David Dent:

Thank you very much, Celina. Okay, so the agenda today, we've obviously just had our introductions, and as I say, welcome to the many guests that are attending this webinar. As you can see, we're going to look at timelines and procedures for this process, the readiness checks and impact on transition of trials, planning and resourcing that's needed, and particularly as our team has been intimately involved and has direct experience, the important lessons learned as transitions are made, and a little bit about our EU-CTR experience. Then towards the end of this hour, we will probably have about 15 minutes or so where we'll be able to take questions in the chat, as I mentioned. Or if you wish to raise your hand also, that's absolutely fine. So, that's what we're covering today.

David Dent:

Next, please. Okay, so Esther, over to you. Thank you.

Esther Gil:

Thank you so much, David. So, I'm going to start presenting critical timelines for EU clinical trial relation. As David has well explained in the agenda, later on we will move more specifically to the transitions with it is the hot topic right now.

Esther Gil:

Okay, so first of all, EU clinical trial regulation is applicable to interventional phase one to phase four trials since 31st of January 2022. In this procedure, new regulatory procedure for submission of clinical trials, we have one submission with a synchronized Member State-level decision across the 30 countries in the European economic area. Also, missions and all notifications, communications must be done electronically through the EMA Clinical Trial Information System, which is the clinical trial portal that we have for doing all this communication with them. And the ET Committee review is totally integrated into this CTIS submission.

Esther Gil:

In terms of rollout timelines, as you all know, when the EU-CTR was implemented, we had a period of time which was optional for clinical trials to be submitted under directive or under EU clinical trial regulation. This was from January 22nd to January 23rd. In January 2023, it was mandatory, the submission of all new clinical trials under the EU-CTR. Then, on 31st of January 2025, it will be mandatory for all new clinical trials and for ongoing clinical trials. We need to have in mind that when we will need to add a new Member State, a new European economic area country after 31st of January 2023, we will need to do the transition to EU-CTR prior to adding a new country. So, we will need to have this in mind.

Esther Gil:

Next slide, please. Okay, some key considerations for the EU clinical trial regulation. In terms of submission, as we have mentioned, there is single European submission synchronized with Member State-level decisions that are covering both opinions, the committees and regulatory authorities. For the request for information, all deficiencies, all questions that may come from them, we have maximum 12 calendar days to respond to these queries. Majority of the cases, these 12 calendar days are converted into eight because there are two weekends in the middle. So, if we don't respond to the questions coming from them, the application lapse. So, it's quite critical and quite important to define well all the actors, all the stakeholders, who will be reviewing all these questions in order to respond on time. We need to consider also any potential translation, any potential reduction, which will be needed from the documentation, which needs to be included in this response in order to be ready for responding on time.

Esther Gil:

With EU clinical trial regulation, we have also a stringent amendment process. What does it mean? It means that as we need to comply with revision timelines, we could have either four to seven slots per year on average to submit amendments, depending on if we receive more or less requests for information. So, we need to consider well our strategy in order to include crucial modifications in the same amendment. All the communications, all the submissions, all the notification must be done through the electronic portal, through CTIS, the clinical trial information systems. The decisions will be delivered by all members' state concerned, included in the trial within a predefined timeframe. So, although we will have a reporting Member State coordinating the assessment, all Member State concern involved in the trial will have decisions.

Esther Gil:

For the clinical trial information system operating model, we need to define very well the user management approach. If there is something to delegate to a CRO, if there is something that needs to be kept within the sponsor. So, all this split of responsibilities must be very clear since the very beginning to avoid not responding to anything. And we need to have very clear as well the CTIS operational user model and task management, who is keeping the different roles if they need to be kept within the sponsor or assigned to one or different CROs. So, this will need to be predefined in advance.

Esther Gil:

In terms of transparency, that's an important thing in the EU-CTR. Approved trial use CTR documentation and information becomes publicly available with very few exceptions. So, we need to be very careful with the information we would like to make it publicly and which information we cannot make public. There will be an established process of reduction or deferral rules, depending on the face of the trial, that we need to think about in advance in order to decide which is the best process for us. We will comment further on this later on.

Esther Gil:

In terms of master databases, we need to ensure that all the products and all the organizations are duly registered in the different EMA Master Database. That's a prerequisite for submission. So, all the database that we have, the OMS, the RMS, Ultra Vigilance, Medicinal Product Dictionary, we need to have all the information included in these databases.

Esther Gil:

Important to mention that the EU-CTR does not imply one English-only dossier. We need to consider other languages for a specific documentation to be submitted. It doesn't guarantee faster approval timelines, except for several countries that we know that in the old directive they were taking a very long time for approval. And mandate one binding decision across all member-state concerns. We need to consider that member-state concerns have decisions and these decisions will be issued per country. So, per country they have decisions from medical committees, from regulator authorities, and finally they will be coordinated by the reporting member-state.

Esther Gil:

Next slide, please. Okay, so what happens with transitions, and we will focus more on transitions in the following slides. As you know, we have a period of time for transition trials from the old directive to the EU-CTR, and this has to be planned carefully, which are the trials eligible for transition. So, all clinical trials with at least one European economic area member-state concern active on 30th of January 2025 need to transition. This means trials with local end of trial in all member-state concern do not need to transition. Meaning that in those trials, which at the end of trial has been achieved, they don't need to transition and their results will be submitted under directive via EudraCT. So, they will continue submitting the clinical studies report under directive.

Esther Gil:

Only trials authorized under directive with more than one active site, we consider active site those that the last visit of the last subject has not been occurred. So, those who have active site on 30th of January 2025 should transition to EU-CTR. Clinical trials with no active sites or ended locally in all European economic area member-states will not need to transition, even where the end of trial has not been reached. Meaning that the last patient's visit has awkward, but there is any specific activity like close of database that has not been occurred.

Esther Gil:

Transition applications should be submitted only to all European economic area Member States, which are active at the time of transition. For instance, if we have a country with no active sites, this country will not be involved in the transition. And an interesting point that we need to consider is that there is no pending or any ongoing assessment in any of the European economic area Member States at the time of the transition. This means that there is no any substantial amendment under review, there is no any country level amendment under review like addition of site or principal investigator change, whatever. So, everything needs to be approved before going to the transition.

Esther Gil:

Clinical trials, which are temporary halted due to safety reasons or due to any other reason can be transitioned when it is planned to continue beyond the end of the transition period. Meaning that if we have a trial which is a temporary halted, we will need to perform the transition. Then once we have done the transition, we need to communicate to EU-CTR that the study is temporary halted. And later on if they need to continue they will continue under the EU-CTR.

Esther Gil:

Next slide, please. Okay, so I will go now through the Parexel extensive experience for all EU clinical trial regulation needs. So in Parexel, we have more than 200 people. Sorry, more than 200 studies under submission, preparation or submitted or approved. We have very well-prepared people, who have been sponsor product owner, has been in the EMA in competent authorities contributing to set up a proper model to have the right insight into the regulation to be prepared for all these activities. We also have an end-to-end trial management system, including Veeva Vault Clinical, which is EU-CTR configured. This allow us to exactly mirror the structure for the regulatory packages that will need to go into the CTIS submission portal.

Esther Gil:

We have more than 200 trained regulatory leaders, who are delivering across all time zones or regions, well-trained and experienced in trials. We have a full dedicated CTIS team, our clinical trial information system submission specialists, with this specific role to meet all the EU-CTR needs in terms of compiling documentation, uploading all the documentation in the portal, regulatory instructor data and so on. Also, a comprehensive global operation model set up. Two years in advance of implementing the regulation, we were under discussion with more than 30 pharma and biotech companies in order to be well-prepared, in order to consult all the models to have this flexibility to support any of you.

Esther Gil:

We have inside our company more than 4,000 people trained, including not only regulatory affairs specialists, regulatory leaders, CTIS submission specialists, but project leaders, clinical operations team members well-trained in these regulation. We use our best practice tools to promote efficiency to timely manage all the reporting obligations. As you may know, the portal needs to be well-monitored. We have our CTIS submission specialists monitoring the portal four times a week, four times a day, in order to control all the notifications coming from any single trial. As you know, all the communications must be done through the portal. If we don't capture these notifications on time, we may lose time for us to respond to this question. So, that's why we manage in order not to lose this precious time. Also including our Veeva Vault, which is a strong trial master file that support all the compilation of the regulatory packages. We are also a exclusive provider for centralized CTIS submission management for several clients, and we provide the prepared support for dealing with their needs.

Esther Gil:

Next slide, please. Okay, so with this slide, I hand over to Celina.

Celina Gonzalez-Colaco:

Thank you, Esther. Yes. So, let us go a little bit to talk about the timelines of the transition. As we know, we have the two possibilities just to have the expedited transition or to go with the full transition. When talking about the expedited transition, we need to think that it has been recently published that the Member State concern will allow this procedure until 16th of October 2024. With this procedure, the maximum timeline for the expedited transition procedure will cover the assessment of a slim dossier. So, a shorter dossier. And the timelines will be a maximum of 22 days. Thinking about 10 days about a validation phase in the case that we have not a request for information, seven days for the assessment and then the five days of the decision. If there are requests for information, we will need to think about an extra time of 15 days in the validation phase and then 31 days in the assessment period. So, we will be talking about around 68 days.

Celina Gonzalez-Colaco:

The Part II is decided by the Member State, so these which could lead in additional days. If instead of going for expedited transition we go for the full transition, well, it will be a load always thinking about a parallel submission. So, Part I and Part II all together. In this case, we will need to have the documents provided under the assessment will be according to the timelines of the initial application in a parallel submission. So, 60 to 106 days, so no less than 60 days. We go into the next slide, please.

Celina Gonzalez-Colaco:

When talking about the transition, we need to think about the different scenario that we can face. Always will be under the principle of harmonization consolidation. So, understanding that harmonization is when we have identical version of all the documents, so the same version of the documents in the different counties and consolidation. We need to think about the same document essentially, but with some differences that are according a specific request done during the clinical trial directive assessment in each of the counties. So, under these principles we will move into different test scenario. It is very important also to consider the need to align or harmonize all the documents, protocol, IB and IMPD across all trials with the same IMP to be transitioned. So, this will simplify when will be a need of a further substantial modification under the regulation.

Celina Gonzalez-Colaco:

Talking specifically about the three scenarios we can face, harmonized documents since the beginning. So at this point, the submission will not need the submission for transition, will not need any kind of substantial modification previous submission. So, we will go directly for the transition. And what it is requested is always to have in the cover letter a statement in which it is declared that the documents were already approved by the Member State concern under the directive. Another scenario will be that we have only few substantial differences in the documents. An example is to have protocol, subject population or age group different in the Member State concern because they have requested during the assessment and the directive. Or also to have non-substantial difference in between the documents. So at this point, the transition will be through a consolidated version of the documents, and this will not need any substantial modification to submit the transition application. At this point, again, it will be needed to have this stated in the cover letter just in order to let the Member State know that we are referring to a consolidated version of the documents.

Celina Gonzalez-Colaco:

The third scenario, it is well-regarded that we need to have an extensive substantial difference in between the different documents in the Member State concern. So at this point, it will be needed to have a substantial modification with better state and substantial amendment, because we will be talking under the directive. So, approved under the directive to have the documents harmonized in between the different Member State concern, and then to move again to the first or second scenario. So to have, again, the transition done after the substantial modification. So, those are the three possibilities.

Celina Gonzalez-Colaco:

If we move into the next slide, please, we can then talk about a little bit the documents. As we have mentioned, sequential submission is not allowed, so Article XI is not allowed. We should go with the parallel submission, Part I and Part II, and the dossier for the transition trial must be based always on the latest authorized version of the dossier under the directive. The Part I at minimum must include the latest authorized version of the harmonized or consolidated protocol. The IB and the IMP, also documents related to the good manufacturing practices and relevant documents and also the related documents to the auxiliary medicinal products.

Celina Gonzalez-Colaco:

For the Part II, as a minimum we must include in the submission dossier the approved version, the last approved version of the subject information sheet and also the informed consent. Only those sites where the clinical trial is ongoing need to be mentioned in the transition application. So, this is the application as a minimum, and as new documents to be submitted will be the cover letter. Also, all the structured data, Part I and Part II, and also we will need to have perfectly identify in the register in OMS all the sites and all the entities that are going to participate in the clinical trial. Also, the state of data protection is a new requirement that need to be submitted with the transition application. In Parexel, we have all the templates prepared in order to provide, accurately provide, all the structured data and to short the time of the submission.

Celina Gonzalez-Colaco:

If we go into the next one, please. Yes. We can think what it is really needed for the transition. Of course, we need at least a minimum set of document required for Part I and Part II. And then it is acceptable for the sponsor to upload a document in the corresponding document slot in CDIS, clarifying that this aspect was already assessed by the National Competent Authorities, and authorized by the ethic or regulatory according to the local regulation under the clinical trial directive. Then, it is expected to have provided by the sponsor of the documents as part of the first substantial modification request as is best convenience. So, there is no limit of time at this point to do this submission.

Celina Gonzalez-Colaco:

But what it is very clear is that it is really important to have in mind the timelines. We need time. We need time to be prepared, first of all, to be prepared to work under the rules of the EU-CTR. Also, to be prepared because maybe there is a need to have the substantial modification previously to the harmonization of the documents. Then, we need to think about the timelines of the assessment of the transition application. And of course there is a very important date there, that is the end of the transitional period. So, this date of the end of January 2025.

Celina Gonzalez-Colaco:

For this reason, I'm taking into account that there are a period of clock stop. We are near to one of them, covering from the 23 of December to the 7 of January, and that we have this period just close to the end of the transition period. We need to think in advance, and our recommendation, Parexel recommendation, is to have the transition done during the first part of the 2024. So, it is recommended to have the transition done before mid-2024.

Celina Gonzalez-Colaco:

If we go the next slide, please, we can talk then a little bit about the readiness of the sponsor and also the readiness talking about the transition. As a general aspect of readiness of the sponsor, we need to think about having a clear roles and responsibilities to support the compliance in EU-CTR. So, for the Part I dossier, for the Part II, the CTIS responsibilities. Also, as it was already mentioned, to have preparation in all the IT systems and adaptation and applicability to work under the EU-CTR rules. It is very important also to consider the need of documents and plates and the collection, and of course to have a planning for the transition from the directive to the regulation. And to have established a collaborative planning and risk assessment inside the organization and with the possible vendors.

Celina Gonzalez-Colaco:

If we go into the next, we can go a little bit into details of the key considerations for the transition specifically, and are the requirements for the Part I and Part II documents. Also, the need to have the master database with all the data that we are going to use to populate the application. Also, all the aspect related to the transparency rules, the importance of the archiving requirements and all the naming conventions. And also, the impact on the safety reporting, because we can also think about, well, having transition in the clinical trials that are applying to the same IMPs.

Celina Gonzalez-Colaco:

So, it is to be noticed and it is very important that as soon as the clinical trial is transitioned in one of the Member State, it is just the full clinical trial under the regulation under the EU-CTR. For this reason, all the rules that were previously mentioned regarding the cross-functional management, the not extendable timelines for the response of the request for information, and the need to have all the roles and the responsibilities established in the CDAIS. And the new timelines for the notifications and the requirements applied to the results of the submission will apply to all the Member States.

Celina Gonzalez-Colaco:

If we go into the next slide, please, we can talk about the planning and resources. For this, I will give the floor to Esther.

Esther Gil:

Thank you so much, Celina. I will go quickly with these two slides that continues because it's more or less what we have mentioned before. So, the considerations for transition trials from all clinical trials directed to EU-CTR are related to business approach, document readiness, public disclosure and sponsor readiness. So, really important to consider a transition per asset, because this way we can align substantial modifications to IB or CMC documentation. Also, if there are any plan to add new countries to ongoing trials after 30th of January 2023, because we need to transition before adding countries. Then, document readiness, harmonized or consolidated versions as Celina has explained in the previous slides, we need to consider all of these reductions, deferrals, all reductions need associated timelines. All translations need additional timelines to consider and to plan ahead. Impact on drug supply labels, documents required under EU-CTR which were not required under directive, and the slim dossier or the brick dossier, which needs to be considered for transition. Then, the next substantial modification in which you provide additional documentation.

Esther Gil:

For public disclosure, you need to consider that after transition, authorization date of trials, data documents are immediately subject to the disclosure rules and make them publicly available. And sponsor readiness, of course, prepare for all the aspect that EU-CTR impact on.

Esther Gil:

Next slide, please. Okay, in this slide, we also repeat what we need to consider for transition. So, a basic checklist. We need to consider which are the studies that must transition according to the rules and timelines, which are the content of the dossier, depending on if we need to do harmonization, consolidation. If we will be doing expedited transition with a slim dossier or a full transition. Safety and clinical supply, it must be assessed in advance to consider which is the type of transition which are more suitable in our case. And if there is any specific information related to safety that must be done in advance or will need a substantial modification and so on. Master databases for sure take into account, have them completed. Transparency rules, deferral or reduction, select between both process, planning for CTIS setup, the roles and responsibilities. Trial master file, very important to have a strong trial master file mirroring the structure of the CTIS. And all the notifications for trial start, end of trial recruitment, start or recruitment end. All the milestone that will be considered for the EU-CTR.

Esther Gil:

Next, slide please. Okay, some lessons learned on transition. This first slide is not related specifically to transition, but there are some accelerated timelines that we consider important to mention. So, for Phase I trials and multinational trials, we have some accelerated assessment for several European economic countries. It does not happen in all of them. Some countries have defined accelerated timelines and some countries are open to do an accelerated assessment without conveying some timelines, and some others are respecting the official timelines for evaluation.

Esther Gil:

So in this slide, we have summarized all the countries that have accelerated timelines with defined timelines. It's the case of Germany that they can assess Phase I studies or multinational studies within 26 days with successful validation. Or is the case of Finland, which will examine it in a case by case trials, shortening timelines. Or Denmark, which also has 26 days for evaluation. In the case of multinational trials, as they don't need to count on other Member States' opinions. A specific case of Romania has also included in their regulation that for Phase I, they can't assess the trials in 21 days for Part I. And then, considering the EC opinions and conclusion, maximum 38 days. The other countries listed on the bottom of the slide, Belgium, Hungary and the Netherlands have not defined specific timelines or reduced timelines, but they will assess these mono-national trials in less time than the official ones. The rest of European countries not mentioned here will continue following the official timelines.

Esther Gil:

I hand over to Celina for the next slides.

Celina Gonzalez-Colaco:

Yes. Those slides are more related to lessons learned in relation to the transitions. Regarding the preparation and timing, should be considered that when transitioning a minimum dossier, redacted version of the protocol and subject information and informed consent must be provided. So, our recommendation would be to submit all the redacted version with a slim dossier. And because you will cover this need for a further substantial modification, so avoiding the need to have this document pending to be submitted.

Celina Gonzalez-Colaco:

Also, before, it's a very important point that before the sponsor adds any additional Member State concern to the transition trial with an initial minimum dossier, a substantial modification must be submitted and authorized in order to upgrade the dossier and to be aligned with the EU-CTR. It is very important also to have a consideration about labelings of IMPs and auxiliary medicinal product, because it is expected the update of the label for those batches that are relabeled after the authorization under the EU-CTR. There is no need to proactively relabel the IMPs. Also, it is a very important point to be considered that the notification and the reports issued under the directive for an ongoing trial do not fall retroactively under the transparency requirements. So, there is no need to be introduced in CTIS.

Celina Gonzalez-Colaco:

If we go into the next one, please. Other lessons learned and considerations are that the EU-CTR templates requirements should be as much as possible already implemented and will cover all the efforts as much as the templates according to the EU-CTR are already implemented will cover the need to have this aligned previously mentioned to the EU-CTR. Also, there is a need to consider the impact of the EU-CTR on supplies labeling and the safe life extensions and establish a robust EU-CTR operating model, including a sponsor and all vendors to be coordinated to track and to check the registration needed in all the systems that are going to be used to provide data to CTIS. Also, to all the CTIS management model. And consider, of course, the transparency rules that as we know are now under discussion and probably will be changed in the early the next year. But it is very important to have all the CCI, commercially confidential information, identified. And also, of course, the personal data.

Celina Gonzalez-Colaco:

If we go into the next one, please. Well, our lessons learned is to have the full dossier prepared as much as possible even if we go to the slim dossier. So, in expedited transitions submitted of document already authorized, in addition to the minimum required document, it will be helpful to have all the data, all the documents prepared in case there is a request for information. There is a need to decide if full transition or expedited transition is going to be applied. Our recommendation is to go trial per trial and to have the consideration on each of them and the strategy to be followed. The EU-CTR number is also something that the Member State can request and to have it included at the time of the transition in those documents in which are needed.

Celina Gonzalez-Colaco:

It is also a lesson learned that the non-substantial changes may not be implemented during the transition procedure, but must be updated in the following substantial modification. Our recommendation would be to have it included in the cover letter but never submitted for the transition. And it is important to consider the differences in the fees payment as it's depending on the Member State policies.

Celina Gonzalez-Colaco:

If we go into the next one, please. I will give the floor now to Esther.

Esther Gil:

Okay, and this one will be my last slide. The two previous slides, just to mention, they were figures captured from the KPIs from the EMEA, that you can check yourself, which is the number of submission transitions and so on. In this last slide, I just want to highlight our experience. We have been managing EU-CTR submissions since the very beginning, since the process was implemented, as we were planning ahead, the preparation two years ahead, the implementation. The status date in November is that we have more than 200 application under EU-CTR. We have submitted 94 trials, including transitions, and we had around 39 studies approved. Even a little bit more as we have not counted the ones authorized in the last week. So, we are happy to support in any activities related to EU-CTR, and thank you so much.

David Dent:

Thank you very much, both of you. So, a little bit of-