Welcome to our today's webinar, Setting up COVID-19 Clinical Trials during the pandemic. Please remember, you can ask questions throughout the whole webinar by using the widget at the bottom of your screen. All questions will be answered at the end of the webinar. Our presenter today is Dominiek Staelens, who's International Project Manager at SGS. Dominiek holds a PhD in Biomedical Sciences and has more than five years of experiences in clinical research. Dominiek, the floor is yours.
Thank you, Yana, for this introduction. So, let me please go over the agenda for today's presentation. So first of all, I will discuss the feasibility of setting up COVID-19 trials. Furthermore, I will move forward to regulatory review and protocol development. Next, site selection and activation, and study set-up as last topics for this presentation. And then finally, I will wrap up the presentation. So to first set a bit the setting of the scene of this presentation. So COVID-19, it's clearly a booming trial industry. So for now, there are more than 3,500 COVID-19 trials, which is quite impressive if you remember that that disease was only identified end of last year.
So of this 3,500 trials, the very vast majority of studies, so more than 3,400 studies are therapeutic and around 120 are vaccine trials. And there are a bit less than 2,000 interventional studies. If we go a bit more in details or in-depth regarding the different phases of the study, then from phase I till phase III trials, there are more than 1,000 trials that have started since January of this year. And currently, there are now a bit less than 1,000 trials that are recruiting, and they need more than 380,000 patients. So on the graph on the right, you see the different studies that have been initiated this year.
And you see in the orange graph, the cumulative number of patients that need to be recruited or have been recruited so far. So as of this month, October 2020, more than 450,000 patients have been or are aimed to be recruited. This is clearly demonstrating that the current setting of COVID-19 studies, it's a booming and a competitive field. Before I move forward to the next slide, so the first topic regarding feasibility, I would your opinion regarding COVID-19 studies, and then to get a better understanding of your experience. So what do you feel has been most challenging? The unclear health authority guidelines on the health authority's expectations regarding COVID-19 trials, the competitive landscape, a high workload for investigators and staff, or other?
I give you some time to reply to this poll. For answers, so I will move forward to the next, or the first topic inside of this webinar, so which is feasibility process. So our standard process is to choose regions and countries based on disease prevalence, right? We know normally the disease setting. We have a short list of sites based on experience in similar trials. And it's mainly the PI who decides whether he or she is interested to participate and if it's feasible to conduct that study at his or her institution. And we receive recruitment estimates, which are based on performance in previous studies. So the feasibility process, you can get a clear picture whether sites are capable to run a study and what are their recruitment projections.
The challenge with COVID-19 studies is that there is no reference framework, right? It's a disease that was only identified end of last year. So we also there is the, there's an unknown evolution of epidemiology and for the country selection, it has a clear impact because it wasn't really known where the biggest incidents in countries will be, or even within one country. There is clearly an overwhelming number of competing trials, as I explained earlier on, and there are different feasibility decision processes at many sites. So that's clearly a challenge to streamline the whole feasibility process. Some centers can't cope with patients and studies, which could bring us to smaller sites, for example.
But there, then you have, of course, the issue or the challenge at least, that they have less resources and less experience. As for any clinical trial, but definitely for COVID-19 studies, the timing is important. Sponsors are eager to start within weeks. As a mitigation at SGS, what we have put in place is we ensure a close follow-up of the epidemiology data, regional and at worldwide level. So the Johns Hopkins data was clearly of added value there. We also increased intensity to contact sites. So we really very closely followed up with sites, and we even recontacted sites when there was a new wave in the region.
Also, the feasibility questionnaire was shortened to the bare minimum to make, well, to facilitate the review process and to make sure that sites are not discouraged by a very lengthy feasibility questionnaire. Also, the starter process, well, we tried to fasten it with site activation in parallel of so the feasibility process. And a well-written and attractive protocol is clearly of added value so that investigators rapidly understand the study that you want to conduct at their institution. Based on our experience, the involvement of the sponsor to connect with critical sites is of high added value. In the next regulatory review, so for standard process, normally we have fixed timelines for review by the authorities and also the ethics committees.
Some countries, for example, in Belgium, there is normally a waiting period to submit protocol amendments. In different settings, we know the regulatory expectations rather well, and we for example know well what is important for ethics committees or authorities in terms of endpoints or eligibility or safety assessments. The challenge here, again, is that it's all new, so it can be difficult to understand the changes in the processes of timelines. Then also there is no real framework for health authorities regarding study requirements, and their review process is also changing in function of the COVID-19 pandemic.
For example, in France, initially in spring of this year, there were shortened timelines for the review process, but then with the decrease in patients and also the very high number of studies, this expedited review process was stopped. Also, another challenge for the regulatory review is that the quick approval process, which is obviously an advantage, has also the challenge that you need to reply very fast. If you want to conduct a study in multiple countries, these timelines not always coincide. It can be difficult to manage the multiple protocol amendments or changes that have been requested by the authorities. As a mitigation plan, in general, as a mitigation plan for a fast start-up, as I said before, some authorities shortened their review timelines.
I've already mentioned Belgium, but for example, also in U.K., the MHRA, gave very, very fast, feedback. So we were able to, to have regulatory approval sometimes within days. As an EMA guideline, they clearly preferred VHP, so the Voluntary Harmonised Procedure, where you combine regulatory submissions in, the, the countries of the, well, the European, countries, so in one. So that would mean that you also get a combined feedback from the authorities. Another mitigation is to consolidate feedback from different health authorities, where possible, of course. So the idea is there that you run the submissions in parallel and that you try to combine different, feedback that you got from authorities in one bigger protocol amendment.
You can also work with placeholders for team meetings upfront so that you can discuss already that you can already anticipate unexpected feedback that you will get from the authorities. Let me to the second poll of this presentation. So have you seen indeed shorter health authority timelines for your COVID-19 trials? Is this the case for you for nearly all of the countries involved, or more or less than half of the countries involved? Not that much, or it's not applicable. I'll give you some time to answer to this poll. Next topic regarding the protocol development, I want to go a bit more in detail on the challenges and mitigation. So normally we have again a minimum level of the disease and the different treatment options.
Also, the health authorities for some well-known diseases, they have guidelines, and we know, again, what is expected. In COVID-19, this is different. So there are new insights in the disease coming in on a continuous basis, and that has an impact on, for example, in an exclusion criteria, but also on the stratification factors. These new insights are also at the site of the standard of care. For example, there was the case with dexamethasone, which seemed to be beneficial in a UK trial, or at least that led to the implementation of dexamethasone as a standard of care in UK. So you need to be flexible somehow, based on the different insights. Different health authorities have also different contradicting sometimes opinions.
And you want to reduce the burden at the site level, so that you want to align as much as possible Standard of Care assessments, yeah, in the best way possible. So because it can be a challenge that if you request too many procedures from a site, that they are no longer interested or they cannot participate because it's just not feasible in terms of the workload for the site. So as a mitigation, what we have done at SGS is we ran the priorities of the assessments to have also input from different experts in the field, also across different countries, because there is also a change between different countries. But I mean, difference between the different countries.
Then, you need to act agile when new information comes available, and it's best to not restrict your concomitant medications too much. So to allow the best standard of care, that's very important for ethics committees. What also is very important is that you have a highly experienced study team, including statisticians and medical writers. Because we have seen that authorities have clear focus on the endpoint analysis and as well as the interim analysis and medical writers, well, of course, they are important because with these very short time-turnaround timelines, there can be multiple protocol amendments. And it's important that this can be written in short timelines and still allowing sufficient time for protocol quality checks. Lastly, you could also work with country-specific versions of a protocol.
If, for example, one of the authorities is very restrictive, but you don't want to have this implemented across the whole study, you can, for example, change some of the in our exclusion criteria. Of course, you need to think about the bigger picture and the impact that might have on your endpoints. A topic I want to discuss with you is the site selection and activation. So, as for standard process, decision-making is done after completion of the process or at least after partial completion of the process. For example, if you want to select some site, it can be an advantage that you first have a look at which sites and what is their geographic distribution across the country, and which sites are interested and are capable to run the study.
Also, our preferred option is to go on site for a site qualification visit and as well for site initiation visit. And for the SIV, we prefer to have all study supplies available so that we can do a check of the goods receipt of, for example, lab kits and IMP. The challenge with COVID-19 studies is that sites themselves, they need to rethink how they will conduct a study, because they sometimes work with COVID-19 wards. So they need to see how the study staff will be able to do all required study procedures working in this high containment environment.
Sometimes, well, a lot of people are working remotely, so not only the study staff, but also at sponsor site or at the CRO site, so at SGS site. So it can be difficult to establish a real relationship with sites and also training of site staff. It can be a bit more difficult if working remotely. Then for site activation, since there can be multiple protocol versions, some sites can be activated under different protocol versions, so from one site to the other one. So that can be a challenge to keep the oversight. So as a mitigation for this fast startup, we have started site activation activities at risk.
So that means even if we don't know that the site will be in the end will be selected or be initiated, we already provided them with a template draft contract, for example, or a study budget, so that at least these activities can already start. Also, for example, we have seen some countries like UK and France, they have a template contract in place, which is very useful because it's one contract for all sites that will participate in that particular country. Another mitigation is, of course, remote visits. So not going on site, but we do a remote SQV visit. There, we still focus on trying to have the highest possible quality. So for example, we work with video conferencing to still have a look at all the facilities that are available at the particular site.
I think I want to discuss today is the study setup itself. So standard normally in other, any other, different setting, we have a stable protocol available for site selection, but also for the EDC, so the electronic data capture and system development. The challenge here is that we have multiple protocol amendments that are triggered not only by the authorities, but also by investigators or competing trials or new insights that can come around. And this fast health authority approvals that we have seen are clearly beneficial, but it also has an impact, or it brings a challenge for the back-end systems because they need to be ready as well in a very short timeline. So the mitigation, what we have implemented there is even more items that we tracked.
So, to really keep the overview of the different protocol versions, of the different requirements in each of the sites or countries. What we have also been discussing is implementing paper CRF at the start of the study. So it's not that we would shift from an electronic data capture system to paper CRF, but it could help to already collect the data before the EDC system would go live. So it would be a temporary solution to capture all required data. And the other mitigation is, of course, mid-study updates of the EDC system. And that was then a fast track so that we can rapidly implement any changes, for example, in eligibility criteria or extra assessments that were required as per protocol.
I would like to go with a quote and a picture that demonstrates the clear need for flexibility of setting up and running COVID-19 studies. So the quote, "The secret of change is to focus all your energy, not on fighting the old, but on building the new." You clearly need to be agile and flexible to set up these COVID-19 studies. And it's not only your own procedures, but you also need to collect as much information as possible from the outside, from competing trials, from changes in the environment, to make sure that the study you're setting up is the setup is done fast and you can still deliver quality.
That is our agenda, and I'm happy to take any questions you might have.
Thank you, Dominiek, for this very interesting presentation. Let's see if we already have some questions coming in now. Yes, I can see there's already a question. Are there any countries that stand out in terms of regulatory approval and setup?
Well, so, indeed, you see that every country, in fact, wants to be as attractive as they can be to run clinical trials, and some have been more adaptive to the COVID-19 situation. So for example, indeed, what I also mentioned during my presentation, for Belgium, for example, there was a very fast approval process. So, they really shortened the timelines to around 10 days to already get feedback on initial submission, which is really substantially shorter than in a normal trial, where you have around one month to receive the feedback. So definitely Belgium was there, kind of, outstanding compared to other countries.
But you see then, for example, that other countries work with a Contrat Unique, so that, for example, in France you have it or in U.K. as well, so that's also shortened then the discussions with site. So it's not that one country stands out, but still, Belgium was, is a good example, in fact, on how adaptive they were to the situation.
Okay, thank you. We already have another question. Do you think some of the mitigations will last past, post-COVID-19?
I think that monitoring will really change, in fact, after the COVID-19 situation has hopefully resolved, let's say. Because, I mean, we also at SGS have been moving more to remote visits. It's not only because, yeah, it's mandatory sites were refusing to have monitors on site, but we also see clearly advantages as well. I mean, it's sometimes easier to set up these visits. I think also access to patient data and somehow that will need to change a bit. I mean, Europe has been or is still very firm on that, also now with the data protection regulation that is in place. But you see that then you get issues.
For example, if you have these situations that monitors cannot go on site, then you cannot do SDV, and that's not... I think that will have to change in the past, or they will need to find solutions to still access this data, but of course, in a secure way. So for example, we see in U.S., they have more access to the electronic medical records and so on. Yeah.
Okay. Okay. Thank you. There's another question: How many amendments did you face, and were the regulatory authorities fast in terms of assessing the amendments?
So, in terms of assessing the amendments, indeed, so that we saw that they clearly prioritized these COVID-19 studies. So indeed, we received feedback within weeks, well, within one week of the submission of the amendments. And what was the first question? How many-
Um-
-on the number of amendments?
Yes. How many amendments did we face?
Well, of course, that depends from study to study, but I can say it's quite substantial honestly. It's there is really one amendment per country you're participating in. So that at least. And the issue is, of course, if you have an amendment you triggered by country A, you also need to submit it in country B, so that can again trigger another amendment. So it's somehow a vicious circle, and that's why I would really go for the parallel submissions, where at least you can combine feedback that you get from authorities.
Yes. Okay. Thank you very much. We have time for another question: Did you experience challenges with international trial as compared to European limited trial, at site and at health authority level?
I did not see a clear difference with running trials only in Europe or if you add, for example, the States or we also have a study that is also running in Brazil. It's very similar, honestly, but what again, what you need to think about is that, I think in general for global phase three trials, you need to make sure that your study assessments that you are requesting, that it's feasible for almost all sites. So don't focus specifically on only tests that are being done in Europe. You really need to think about the bigger picture to make sure that you can collect all data from all patients, irrespective in which country they are enrolled.
Okay. Okay, thank you very much. Maybe another question. Because of the lockdown in various countries, how did sites ensure patient visits for the endpoint evaluation visits, like imaging assessments, labs, et cetera, critically, which cannot be done at home or by means, or by other means?
Well, so far, the studies that I have been managing, there were no. Well, all visits have been done so far, so we have one inpatient study, so that's obvious that the visits can be done. For another study, patients had to come to the hospital, but that was still feasible. So, so far, yeah, we didn't, we don't have studies that, I mean, that the patients had to stop their treatment. What has happened is that the studies were put on hold, so that recruitment had to be stopped for particular studies, that they could just not enroll any additional patients because the site had to focus on treating COVID-19 patients, which I think is obvious.
Okay.
and understandable.
Okay, thank you. Maybe we have time for one last question. Do you know if trials needed to terminate early due to the competitive environment?
Yes. Well, terminate, I don't know, but we were informed about some sites that participated in some of the studies we have been running, that they stopped the setup of other competing studies. So I don't think it's really termination, but it's before the first patient was enrolled, that eventually they stopped. And I think that has some way. You could see this, in fact, it was in Europe with the second wave that was, the first wave, sorry, that ended. So in summer, there was a decrease in cases, and then you saw as well that some studies stopped what you would say, in the initiation phase.
That was also something that we were always focusing on, is we knew or we were expecting a second and probably also a third wave. You really need to think a bit longer term to make sure that your sites are ready to enroll patients once there would be, again, a peak in COVID-19 cases.
Okay, perfect. Thank you very much. I think we're running out of time now, unfortunately. So, Dominiek, thank you again for your presentation and for answering those questions. And, thank you to everybody who was attending.
Okay, thank you. Have a nice day.