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Ron. Welcome to the National Research Collaborative Beating 2020. Thank you for joining us. We're very excited to present our webinar research red tape. What can we learn from undertaking research in a pandemic? We have the amazing opportunity to hear from some of the orchestrators off the recovery study on the coated search Collaborative. Before we start, I just like to go through some simple housekeeping. On the left hand side of the screen, you'll see a reception tab, a stage tab on the sessions tab. Our schedule and President Video Gallery is available in reception area peas. And sure you have a look at the high quality research being conducted around the country. She's also filling up whole, which could be found in Paul's tab to indicate which field work which we'll do. You work in our speaker's a hosted in the stage tap. Please use the status chat for questions only, and any other questions or conversation should be held in the event wide chance. After that, the event will have coffee shops, which will be hosted in the Sessions tab. Please join us there for conversations about tonight's contents on after the event will be sending feedback links. After completing it, you'll be offered a certificate of attendance. Just make sure generating a tendency ticket a board at the bottom of the form. Now I'm pleased to introduce our chair for the evening. Jane Blaze Be is a professor of surgery at the University of Bristol. She's the director of the Bristol Center for Surgical Research, a multi disciplinary center who's overall a miss. That design developed and delivered. Studies evaluate surgical interventions to inform evidence based practice over to you. Thank you very much, Emily on welcome allowed my welcome to everybody to this and our CME eating, which we had hoped to have you all coming here for a drink in Bristol. But we're very much hope that we'll be able to do that face to face next year. It's a real privilege to have the to be able to chair these two projects for you and talk to you all about them this evening. Hear more about them because the burning and team who fled the coated search project of work so brilliantly over the years on it's just I'm so delighted that Martin Landry conjoined us from the recovery trial, which clearly we are all individually very grateful. To have run from the new came with such fantastic results for the whole world. So it's very exciting. So I'm going to a hand over. First of all to James, gays be and to Elizabeth Joanna James's going to present but just the highlights of the study. And then they're going to show a video about how on earth they managed to so quickly and so efficiently and so well run the important Covitz surge study. Thank you, James. Thank you very much, Jane. It's a It's a pleasure for the three that's there to be here this evening. And so we've been told straightening not to focus too much on on the covert search. Nitty gritty results today and we're gonna try and give you an overview off the process and how things got set up right swiftly at the start that the pandemic on give you a little bit of a insight into how these big international studies come run at scale as we've got a little elevated pitch for you first, just the one over on just there. You know, maybe the top five lessons we've learned from from Cape. It's Serge. I think the first thing to say is that this, you know, this is not our our work but work that's owned by thousands of clinician, surgeons, trainees, anything a Laronde, the world on the reach. This network has now expanded, see over and Hunt, including over 100 and 50,000 patients across the study and portfolio on with over 15,000 surgeons. That's about three times larger than the Large Hadron Collider collaborating groups. This is the largest elaborating group we think ever put together in for a scientific study, and it went out on the work of every single individual. Within this, it really wouldn't be impossible. And the other survey important group of people to thank for the work that cave it searches done really, is there is the funders, and it was a really tricky year for for charities and funding organizations. Everyone's focusing on on cable, but these organizations put themselves out there and supported us a really crucial time at the beginning of their the pandemic so big. Thank you too with these groups so quickly elevated pitch number one and there was a huge amount of elective cancellation of surgery around around the the world in first base pandemic and the estimated in a modeling study that about 30 million operations were cancelled in the first three months. The pandemic and this will be expanding further and further still. And the reason was, of course, I worry about the risk off saw Scooby to the Corona virus infection in the parotid setting. Lizzie, just give us the elevator pitch about the cold with the amount of paper. So hello. So after that, there was a a real need to understand how this novel coronavirus affected patients on the need to gather patient level, high quality perspective data. So we started this cobalt study on as firstly, looking at patients with peri operative saw Scooby to diagnosis to seven days. Four or 30 days after on what we've found in the 1st 1000 patients, which was published in The Lancet, demonstrated that off these patients there was a very high mortality rate of 24% compared to previously cited surgical mortality rates. On off these patients, 51% developed post operative for marine complication, which in itself had a 38% chance off a 30 day mortality. The patient's most at risk were male. They were elderly over 70. They were sicker off a grade 3 to 5. Cancer diagnosis and surgery was more risky on emergency and major surgery. On our conclusion after the first analysis was that post operative complications of mortality is higher in the specific groups on that thing, patients should be protected. Thanks, Lizzie. And so then we know that you know, cells could be two in there, perhaps of setting was really severe. So our second study, which was cool, covert search, cancer or this included patients undergoing elective cancer surgery know that protected counts a surgery type during the early phase of the pandemic. And we looked first that the operated patients on ways that surgeons around the world we're trying to protect patients from from cells gave you to infection on. The first thing we examined was the role of these covert free or covert light hospitals that we've seen being set up. Me ask, did the's kind of covert, said covert. Three surgical pathways actually protect patients cause they're huge headache, a huge administrative efforts and take it a large amount of funding on what we showed in this paper that was published in the JCO a couple of months ago. Now we demonstrated that there was this consistent evidence of covert 19 free surgical pathways reducing the risk of infection on subsequent Paul me complications on death. And this works whether or not the community rate was was high as it is now a low. There's still this benefit that we saw. So that was the sort of next phase of the project saying, You know, you should set up over 19 3 pathways to encourage surgical safety on the next point in the story of passion onset to Joe for our third elevates bitch. Thank you, James. My name is run. I'm also in the research fellow is working in the collaborative. So from this study about cancer patients being operated during the pandemic, one of the research questions that the surgical community head during the first wave and now a swell is which testing should be doing to kind of mitigate against asymptomatic carriers to carry the virus and have pulmonary complications after surgery, which we have seen that carry a high risk of mortality after surgery. So we've compared different testing strategies with compared patients undergoing swap testing, CT both or no testing. And we've come to the conclusion both in the adjusted and non adjusted analysis that actually swap testing is the one that is more more better correlated with lower pulmonary complications after surgery. So the recommendation is actually that's walk Testing. Is is the best way to prevent asymptomatic carriers to to carry the virus and have complications after surgery. And we've done some some sensitivity. And all this is just for the patient's being swamped. And we've calculated the number needed to treat comparing patients undergoing minor and major surgery and in in high and low incidence of covitz areas on Gleevec came to the conclusion that swap testing is is relevant overall. But more important, when patients are undergoing major surgery, especially when covitz, the community incidents of Cove it is is high, and the cut off for this was more than 25 days for 1000 100,000 population. So this is one of the research questions that we also took from from the cancer study. Thanks J E. So yes, so we we've had this story lots of operations cancelled because of this fear of peroxide infection, but we think that this data gives the evidence needed. Teo Upscale surgery safely through Cobra 19 research pathways on routine preoperative testing and I encourage you a lot to download are on post pandemic Recovery report and from this language, details in Technicolor Glory and created by Dawoud. And he's a burning a medical student and corner. Jonesy's a trainee in Bristol, and it's a very nice report showing sort of a new review all the dates there without further Gene, and we've had done a little fights. I chat with the three of us in there, a needle bang Use the study chief investigator on Well, if it's okay feel we'll go over to the video tape. Teo, watch that back to do Put questions in the stage. Chat any anything's. We go along. Hello. Thanks for joining us today. It's a pleasure to be here for this year's National Research Collaborative meeting on We're going Power 0.3. So we're gonna do a discussion amongst the central covert surgeon banishment team who were here about what went well and how we got it going so quickly on where we can improve on what the future vision is. So my name is Neil banging on. I'm a consultant. Colorectal surgeon, University hospital Burning gun. I'm a senior lecturer in condition scientists on And I saw a grew up through the national collaborative, which is really got me Teo where I am So I'll let the rest of the two you introduce them stealth cells. So let's start with Elizabeth. I I'm Elizabeth Really dizzy. I'm a little distraught, and I chart doctor or research fellow in surgical innovation on again. Also involved in a club, too. Research from a essentially level on, uh, really excited to be him on over to Joanna. Hello. My name is Run A a general surgery trainee from Portugal, part of the PT Search Collaborative. A swell and now doing research in the global surgery units in Birmingham. Glad to be here today. Last but not least, his James everybody I I'm James again. A doctor will be such following global surgery, working and burning in. I'd be involved in started for a while to come out eaten now, doing some great well surgery. Worked with a new on the team. It's actually so it's been it's been a tricky year for all of us. And I think what? We're all aware that trainees have been on a particular roller coaster. Repaving rotors changes in in training, and we feel that on we feel for what's happened to the patients is well, but you know that the train, from my point of view, the trainees have shown in the in the research and a cave it's Serge side and they produce is data, which has been pretty amazing on has gone around the world. So let's just explore that. Let's start with Joanna. Um, if you think active to march, what's your take on on how this started and how you got it all up and running so quickly? Um, it was actually quite a quite amazing sets up in terms of how how could we get a lot of efforts together to set up a project so quickly? And I think one of the main things there is that because everyone was very focused on this single project, and for a while there were no side projects, and all our attention and efforts were towards this particular project, and obviously you can't simulate and replicate those conditions for all of your projects, but you might learn from that. And you might want to in future projects for a time that particular time window. Focus your team on something and and kind of put all the projects in standby so you can get networks and projects sets up really quickly to flip it just to the other angle. James just looking at this from the other side. So you went, Are you and I went on to these covert rotors. Didn't weigh in, um March, April, May and a bit of June. I think most of the people listening today probably ended up on some form of Cave in rate, and they were emotionally tough. How did your balance doing all of this coded surge work with being on a on a caving greater? Yeah. As you say, it's tough for everyone that I think that has been working. The cave in environment was quite a stressful time on exhausting for people, but actually these climbers of data projects was something really positive, which came out of all of the chaos around cave it. I think it really built a community and people felt part of something, and it's saying which they could, you know, take him and said that this was there, like, pass in a border cave in effort. And so I think, actually, spending some time outside of work on this, I think was was really positive. And certainly that's the sentiment I've had shared by by others. Tea. I'm Lizzy. Do you think taking those two things into account that people busy and tired But you know, people wanted to take part in something? Do you think that contributed to the range of specialties who took part? It encoded because you might want to summarize. But I think I think we have representation for every single specialty. Yeah, we definitely did. There's probably Waas across all specialties, a degree of almost nervous energy, as this own foreseeing wave started like sweeping the entire world on all of our lives and works. Lives were changed on people were looking for something productive, a positive to channel their energy into, and also to get some answers as well on it certainly did, you know, with the entire social community, because we were elected by this. I think that very much helped us answer these critical questions on get caucuses off the ground and so so well, on that. On that point, we'll flip. It will go backwards. It James, I like to hear from a what? If you want this, This is about the design fades. So, you know, it was designed very quickly. Um, the first thing I say is we went cross specialty. Would you recommend people to do cross specialty projects? Or do you think that is to challenging and bang in mind that you might be talking to people working in smaller teams? Now it's really a point. And so I think in general, what we've learned from this and previous budgets is actually the kind of bigger ticket topics which cross over multiple facets, especially and surgical specialties, and perhaps lean into medical specialties. Critical care anesthetics. Actually, finding those borders between overlapping men diagrams is a real strength. That means that the research we create is meaningful to mawr. Two more patients who certainly cross specialty working. I think it is a really strength, um, Inko. This is cancer, which was sort of power projects. We work with the leaders in lots of different specialty areas to design kind of spoke additional parts to see a refs that could give specialty specific in in sight and that and did have its challenges. You know, that's a lot of data to handle and correct on get to get right. And why do you think that kind of cross specialty method of working its thing we could definitely learn from for the future, maybe on this and you? We can also say that in the design face it was quite productive and quite meaningful for the design face to have feedback from a collaborators no only leads, but actually collaborators from different countries, different settings, different specialties. And when you go back with your ideas, you're rough ideas to your collaborators. You do get a lot of information back and feed back. There is always a bit of noise when you do that, but you do get an idea off what is relevant to a broad group of people and actually you design the research questions for your gout puts later on to be more generalized able in terms of what they can influence in clinical practice on subjects come back. You on that with the you're talking about the design phase and you've had a lot this information back to people. Um, I'm also thinking of our full control, which is closed and was closed in record time with really high data completeness harnessing that all together. I think we had one of the most efficient design process is for our protocol on our CF, which is which of the report forms people fit it from your point of view. How were we so efficient in a protocol in the Sierra over such a complex project. So I think it probably takes a lot of responsiveness between the team designing the CRF, being able to absorb the feedback, get back to the collaborators again. So this kind of short term, you know, go back and forth with your project kind of speed you up and allows you to have a, you know, a complete it or full CRF quite quickly. And also, I would say that one of the main things that we always I'll highlight it to people because these were was always going to be a large scale global scale study was Please do make sure that we are only including data points that we are actually going to use. So trying to make our CF says Shortest possible in is directed to the research questions possible was also very important to kind of move forward to quickly. So let's weigh, sort poured over. If we look at the cove, it's a project. The first one. We spent a lot of time producing a very short protocol on every day. Two point that went on to the CR. If we saw a focused it down and figure out if we needed it or wanted it, do you think, would you recommend other people to do that, or was that specific to this project? It does depend on what you're aiming to do, but in general, with our experience every and the side off simplicity, designing it to answer the question you set out not too broadly. Try and gather as much information as possible on also ease off use for your collaborators on also, as a German James glued to listening to the feedback from our collaborators as well those on the front line. What questions they need asking so amalgamating all that together toe answer. Just the critical questions. Waas What we found the most successful model on Lizzie's point I guess one of the other things we did for the first time here was to build some, like black spell it into the protocol. And so we were able to kind of change the political change to CRF. So on we built that way wrote that into the critical that this would be responsive, new changes and adaptation. And that meant that we had, like, a form or second phase of the project. We introduce any data points we took small that weren't working. And it's the whole kind of feel fast fail early. Once you've got started, it's much more easy to learn for experience. So perhaps that said and useful, ask him for the future. I'm gonna ask you each a specific question about delivery. So, Joanna Dissemination Committee, What was it? What is it on? Is it useful? So I think it was the first time. We've probably, um, gave it that name dissemination comedy for you always have this group of people that kind of buying into your project get and kind of disseminate, you know, spread the word about it and everything in this project because we wanted to go big scale in global scale weigh thought about this dissemination comedy by being a group of people who would be leading their own countries setting up for the study. But we made it very flexible in inclusive. So, for instance, we didn't restrict it for one single leaper country. If if people could get help from other parts of the country to get the whole country involved, for instance, we would allow more people to join within. Let's say Germany or South Africa or any country on days dissemination comedy also include people who would be representatives from international societies who could work across different countries. And 78 that the studies and and the results across different countries and continents. So I think it's It's a very flexible platform where you have people who are quite enthusiastic about about the studies and that the, you know, how can you turn the studies into clinical practice. So I think it's probably a lesson that we're going to take for the next studies. We should always have a group of people recognize group of people who have this roll off spreading the word and also getting back to us with their struggles, what they're finding difficult while delivering the study so we can kind of doing it. Treated development off the study. James, this term of a data transfer agreement comes up law. What is a day to transfer agreement on? You know, if I've got a team of three or four registrars shr on one of your project across the country, maybe a couple of the countries bang in mind that we had the full support of the chart, you know, on global surgery. And for those who don't know that's based in Birmingham, its core funded by the in our chart. It comes with a lot of research managers who help with with with with the technicalities and navigating through a university, which is really one of the ways we deliver these projects. So would you recommend if I was doing a project and someone from the United States drops a day to transfer agreement? Would you recommend that I take that on a Was that step too far for me? Is an individual training surgeon? Yes, really good question. It's one that's perhaps limited some off the work that's happened in North America, for example, in the past, so traditionally we struggle with America in Canada in terms of building big collaborations because they often require institution specific data transfer agreements, and they're effectively agreements between whichever institution is collecting the data on whichever institution is hosting the data and sponsoring that study. It's basically agreed to some common rules about the security and confidentiality on how the dates will be held and disposed of over time and what we did with in this project with the have a set day transfer agreement that we did find that that starts in collaboration with Far without a needle office. It didn't make a huge amount of work in that say, I'm sure we can share an example off, for example, on. But once we had that day to transfer agreement in in in place, you're quite strict with sites and saying that if they're needed to be changes to this or they needed to adopt their own dates transfer agreements, that we wouldn't be able to accommodate that at this at this scale. So if I was starting a project and want to work with three American hospitals, you know, maybe it would be feasible. Teo, think about doing spoke days transfer agreements but it might take months on end on. But if I was thinking about doing a project a large scale when hospitals that might need these, probably what I would do is to set a date transfer agreement at the start, which is consensus and would would meet regulatory requirements on then make it a part of the study. Inclusion that sent us have to be able to agree to this without any changes if they're happy to go ahead. Worked well for lowest studies such as this with observation of days own on on, um, I've and then Lizzie can. We just talked about Red Cap a bit because people, you know, we run our studies on red cap when people want to run a red cap on. I got a lot of people approaching us about how they can do it. What are the costs, etcetera? But But my my question is this Is it possible for a great group of trainees to set up a run their own red cap? He he does a red cap based project need dedicated administrative support? No, it's absolutely possible for a group of trainees to run it. Normally, Red Cap is still centered within or research organizations. However, the day today running's off. It is easily deliverable, with relatively simple training bye trainees or anyone who's interested in medical students as well. It also means that what we were able to do was have quite close communication without collaborators. So there was immediate feedback. We had a very good sense off the front lining issues that people were in country we could directly because we had a small team that was dedicated to demand this where which were just it were able to pull out things and information if we needed to. So we were able to move this project at each step, despite it being a huge project face every challenge as it came along on. It was also realized around the database, So yeah, definitely can be delivered. So, um, Lizzie, sometimes you need some soft money just to support the Red Cap server and a bit of administrative time as a group of trainees. Is it realistic? Got and seek 5 to 10,000 lbs from someone. Yeah, absolutely. There are multiple organizations and charities who will be able to support small grands that will get a study off the ground just so that there is some data base access on. Perhaps the line touched administrative access. A swell you would need. Teo developed your question, Know which patients you want to benefit and then approach the right organizations. But the opportunities are wide on A very much available, so definitely would encourage you to seek that. Thank you. I'm gonna I'm gonna wrap it up there. I mean, as with these things is lows we could talk about on There was some nuances of how we got the thing up and running so quickly. The international communication, how we work, vial a gyn or what's AP groups on the various levels of committee that we have to set up to deliver this kind of democratic project. But we'll have to get into those another time. You know, we recognize this as being a responsive project that the surgical community, the global served community called out for it but actually working at those times scales and moving quickly with short of protocols on adapting to whatever the local approvals and necessary. So in the UK, most of this is done Order and service evaluation. Some places internationally they did get ethical approvals. Uh, but having that flexibility around what the approval is, having some flexibility around time is one of the other ways that we got this up and running so quickly. We are about four people of the whole code search team off off which there was a, you know, by necessity of Central Management Group of burning them. But there were international committees and and different people feeding in, which is complex but is the only way that was able to happen. And we really presenting on behalf of those people today. So we like to thank them very much on we be lighted to hear from any of the trainers who wanted to get more involved in in covert search on the work going forward as we looked at the find your vision of what it could be, but for now, thank you and goodbye Hi, very much James on a kneel on Lucy and do an on for that video on for a little amazing what you've done with the Cove. It's such project on. It's made such a huge difference too. Well, surgical practice worldwide on display in to see of all works so well. We don't have any questions at the moment from you. Also, what we're going to do is we're going to move on now to the next presentation and then we can pick up questions at the end of Martins talk on. But I'm just so pleased to able to be able to introduce Martin Landry to Who is professor medicine and epidemiology in Oxford on I've known Martin for least 10 years, I think cause I we have the opportunity of working with him in the NMR See methodology helps project That was done a few years ago and at that stage I kept hearing from the Oxford Group or we do big trials. We do big trouble that matches his large scale trials on. I wasn't really sure then what that meant on. It's just been brilliant the last year actually seeing that first hand as he's run the recovery trial and I've had the privilege of kind of overseeing in Bristol, I'm being on the receiving end of such a well organized, incredibly important project which has bean adapting as it's gone or really fast, and making such enormous impact to one of us is just incredible. And in fact, I read up Martinsburg. You might imagine, in order to introduce this and what he says at the end of it, I'm actually certain it's wrong and it needs to change. Mountain Is this here that within 100 days, the recovery 12 showed convincingly that dexamethasone reduces mortality by one third amongst the sickest patients. And then he goes on to say, and that was adopted into standard care worldwide within weeks of its announcement. And that's what's wrong. It was adopted worldwide in standard care. Within days of it's announcement, and certainly in Bristol, we literally had a drugs meeting within 48 hours and got it sorted out the following week. So I think you need to put within days Maarten, not within weeks. So I'll shut up now and hands over to Martin. Who's going to tell us about how on earth to want to take research? It's matters to patients, to health professionals and to the health service worldwide in a pandemic. Thank you very much, Martin. Well, thank you very much. And it's a pleasure to be with you. I I recognize that Kobe, it is ah, new condition for us all, and many people haven't worked in infectious diseases before. That includes May until the beginning of March. I've never done any research in the context of infectious diseases. Little over a clinical trial has been something with learning experience for me. But I thought I'd share some of that experience in some of the background and how, what? How we got to where we are now and I take it back to early March 1st week, also in March, when we were hearing the stories from more than Italy of the devastation that code was causing over there. The challenges with ventilation, whether enough into the ventilators, enough beds, serious rationing shoots your stress in here in the UK we were looking ahead to the vision off a massively overstretched health service. We didn't know if you have enough beds, enough staff in the ventilators, huge time fractures on frontline medical stuff know any time pressures, but huge personal stress, given that they weren't any treatments that we need, that we knew would be helpful. And they're huge numbers of unwell, anxious, elderly and and alone because of the infection control measures patients and at the same time you realize that one in four of those hospitalized patients will not make it out of hospital alive, for those patients are sick enough to require intensive care, then that might have wanted to. You wanted to. And there was no certainty about how to treat this. A new virus and new disease, literally hundreds of candidate drugs. Many, many opinions, both from the scientific community, that clinical community on but also in the media in the in, the social media on in particular even form some very hope. Hope for high profile politicians making claims that certain treatments were miracle cures or others making claims that certain treatments we're going to be outright dangerous and shouldn't but not be used. But all of this was hype, hope and speculation on there was no evidence. Few small little trials, which became ah, spun out of control in terms of their impact as an inconclusive and the Mice child's. And it struck me and the team. You're working with me in particular, Peter Hobe. It's unlikely to be a single big win. This wasn't something like back to her meningitis, where a single drug was going to essentially turn something that was fake into something that that was easy to survive. This was going to be much harder. We need perhaps a multiple treatments with modest effect, as we've seen with HIV, with tuberculosis, with heart disease with diabetes. And that means last year. RANDOMIZATION. Now this is Ah, work I open on. I've been working for the last 10, 15 years on the whole area of regulation. If I was giving a talk last this time last year, I have talked about the advances in data, the need for regulation to allow us to do smarter trials and so on. But I still just picked out this one piece, which is about what a high quality clinical child looks like. This is working. Actually, I was involved in and apart lead with FDA and others and came up with the definition of a high quality. Trying is defined as the absence of errors that mattered to decision making. Another words, and so I to interrupt teach. If we're not seeing your slides of the moment now, did you know it has been I suddenly thought we must be needing to see this definition so that that's a fault in my ability to navigate the system. It's okay. It's great listening to tour. I help you with it. I think it's better if you have something to look at. That's not may. So there you are young. I will go back to the beginning. Briefly. Apologies. So I just just to give you the the context. I've been very clicking through these. So this is the beginning of the year, and this is clearly the epidemic well known to all of us, as I say, the impact on lives, Theoneste certainty and the need for randomization. So here we are. Quality. What quality in clinical trials, absence of the errors that really matter. Decision making. In other words, there's that seriously impact, the safety of the patients or the credibility of the results. And it's not because we want results just cause results are nice. So we want a publication, the lancets or whatever it was a constant focus on. We need to solve a personal patient health question in a public health question, we need to sell the crisis. That was what we were after was results that would change the trajectory off of it. And so when you apply that in this context, off the overwhelmed health system, the very large numbers of sick patients and so on. Hey, listen, keep Interpol's. The first was we had to have results that could rapidly impact on clinical care. You have to consider the well being of the patients, obviously, but also and you'll never see this in any GI CPK course that you might do. We have to consider the well being of the staff on the availability of the resources. So that really drove us to focus only on what matters. Anything extra went. Anything that made it harder to randomize went so away. The usual traditional practices, the extra baggage that so many have added on over the last 20 or more years. We had to examine that and say, Is this necessary? Will this drive towards a high quality trial built with that was this was clearly gonna have to be Ah, whole team effort on that whole team, as I'll show you a bit later has turned out to be truly massive on. But it seems to me that in the context where Cove it was the one and only issue in every newspaper in every conversation on. We were trying to do a clinical trials, which some sort of sounds somewhat scary or used to in the context of this pandemic. There had to be transparency and openness about everything we were doing. And so in the night of March, Peter and I started writing the protocol, and I had on my desk two papers. This is the first of them. This was from 1984. Uh, why do we need some large simple around my straps to be clear? This in the paper never argued that every trial has to be enormous or every child has to be simple. There are lots of reasons for doing other types of child, but expected particularly look at the last sideline or last sentence. Particularly large, simple trials could be used to suggest the possibility of those are pretty, but the that's on mortality or various widely practicable treatments for common conditions. What was interesting was really read that this paper it it's only about four pages long. If you replace the words cardiovascular or myocardial infarction with cove it or coronavirus, everything else pretty much slots into place on, Of course, that same group that did that. The master demonstration trial of the of the ice is two trials of acute myocardial infarction. In the late 19 eighties, this trial came out actually just a Z. I entered the clinical years of medical school, changed the practice of cardiology overnight and actually changed much of what we're doing. Clinical trials on the left. The famous one page case report form on the right. Very clear, compelling results on mortality showing that aspirin it's Onglyza. It's a beneficial if you use the two together, you the benefits are additive. Very clear. Results change practice. Very simple trial to do but stuck to the scientific principles. But what I like is this has a paragraph which is on the front page of the protocol again on my data as me right in the recovery one by far the most important determinant of the success of the child is the extent to which the responsible physicians and nurses choose to enter their patients. Has the extra work must be on these absolutely minimal. How can you make it the ultimate goal as easy to randomize toe hydroxychloriquine versus not as it is to prescribe hydroxycloroquine or not that's where we're aiming to get, then on. So the recovery trial design is every hospitalized patient who has Crohn. A virus that you would want to treat is eligible for this study. Grown. A virus can affect us all. The trials open to us or the youngest patients under six months old is is over 102 years of a 40 or 50 pregnant women, a similar number of Children 18% of from black Asian of minority ethnic groups, 60% higher co morbidity, 20% over the age of 80. Another 20% between 70 and 80. It's open to everybody, and the focus was on mortality. Clearly randomized on. We had a one page case report from one page of randomization one page at 28 days or discharge on then, Because this is the 20 twenties and not the 19 eighties. Think it's through. Too many different routine health care data sets the consent form as an example. There's the one page consent form. I want a copy of screenshots of the information sheet, but it's two pages, and it was focused on informing the patient, remembering that these are patients who are seriously sick alone on the last thing they want to do is read, as was a case in one pharmaceutical company trial. 8000 words off, small print out for before signing consent form. Here's the design at least the initial design, As I say, Patient's admitted to hospital with grown of those, um, infection that that you would want to treat with one of these patches on these drugs if they worked on, we started off with four different treatments. You get any one of these or no additional treatment? In other words, all the usual NHS care, but not one of the drugs. The Pinna very of Tom A. There's an HIV treatment. Dexamethasone, we will know is a steroid hydroxychloriquine main area and rheumatological conditions and azithromycin we think of is an antibiotic but does have some immune modulating properties, which might turn out to be useful in the context of this disease. 28 day mortality from the outcome, As I said, And here's the record linkage. I have to say that I never thought this was gonna be possible at the beginning of the year, and I've been working in health data for a long time and particularly around trials. But there's 1, 14 15 20 different data sets from different parts of the country are looking at hospitalization data survival data intensive care units, audit data and read a registry data but also looking at Covance specific information. We took the principal that if the any chest was collecting it, why would you spend time asking the search noses or conditions are at to record it or bothering patients who remember seriously sick to ask them yet again information that you already know the NHS already knows. How can you enhance both the background information you have on the foreground? Information about what happens to people? We have permission for this for not only for 28 days, which is the primary outcome, but the six months, which is a pre specified analysis on Actually, for 10 years of follow up, we knew nothing. Nobody had ever heard of long covert when we started this trial, but it seemed to us we needed to understand the long term effect of treatments. So this child started rapidly on the night and 10th of March, we wrote the coach Coal on the 19th of March were recruited the first patient eight weeks and nine minutes later randomized the 10,000 patients in the 1st 100 days that randomized essentially 12,000 patients. Every huge trust in the country from the Westerners of Scotland, too. Southern tip of Cornwall from Northern Ireland, across the the east coast of each Anglia are involved in this trial. Some of created last number, some small numbers. But it really is a whole nation. Whole team Colette HS effort. And so we got within those 1st 100 days, the first results. So on the left hydroxychloriquine on the right, in the pit of air, the HIV treatments remember how doctor Qualaquin had been had widely promoted. It was used on an emergency access process in Francais in the United States. It was extensively used in Brazil of juice in India on at least three presidents had had actively advocating for this is the treatment as a miracle cure? Turns out, when you do the trial in patients, we've got codeine in hospital. The treatment is completely useless. On the right is a beta. Is the HIV treatment the pin of ear? Perhaps less famous but equally widely used. These were 1st and 2nd choice or 2nd and 1st choice, depending which guidelines you looked at in national guidelines. In about a dozen different national guidelines around the world based on expert opinion based on my no biology or something turns out not based on fact, the treatments are ineffective and have been abandoned. Dexamethasone know the 16th of June, and this changes where you were talking about earlier on. That was quite some day. I have to tell you when you know this result and you know that you're about to do a press conference to announce it, and you know that the drug cost 5 lbs for a course of treatment is on the wh Essential medicines list is available in pretty much every pharmacy in pretty much every hospital worldwide that it reduces the risk of death by a third amongst the sickest patients by fifth amongst. Those require lesser forms of a spiritually supports that such as oxygen that's quite a that's quite a thing to know and be about to tell people on one of the things that take through your mind and beat and I were talking about is we paste up and down the corridor is you're gonna be damn sure you're right now. The evidence is very, very clear. Clear about evidence of benefit. Overrule but very clear evidence. Also, if this trend works best in the sickest patients renounced that it's out one PM at. By five PM, Chris Christie and the other chief medical officers had written to every hospital saying, We think that should be standard of care on, but it's one of those occasions where you can say at lunch time in our results. It's policy by t time. It's saving lives by the weekend on. Yes, it did get rolled out over days on D actually, weeks. It took some time for it to filter through all the way to the wh show and whatever else. But by then, people were doing it. This was something that people could do, and it's still the only treatment known to save lives in in Cove it It would not be known if it wasn't for this child. We actually had people writing to HR A or roll colleges or to the university, saying You should not be you doing this trial because this treatment is dangerous is dangerous to suppress the immune system when people are fighting an infection. Now, those arguments were well reasons, But the uncertainty was there because there are also other people using the steroid drugs. We've had comments back. Just I don't know why they bothered studying this. We've been doing this in Spain, wherever it is for years anyway, The answer. The answer comes. There's uncertainty, Randomized. Get a clear and compelling results on, then enact on it. And so, people in the second wave off the coast of the Kobe pandemic off benefiting from the experience that the the knowledge gained from those people in the first way. So here we are. Um, uh, we started off with four different street mints. I've told you the results for the pin, uh, verified rocks o'clock. It doesn't work in hospital patients. I've told you the results that exercises only very, definitely does in those who required spiritually supports the Zithromax that my son arm stopped a couple of weeks ago. So those results are likely to be out really quite shortly. And in a sense, you could say, Well, that's job done. We finished. But it actually, of course, let's recognize you only got one treatment that treats the sickest patient patients on reduces risk even in the sickest patients by a third from, say, 40% to 28% or something. That's still means an awful lot of patients on I to you end up dying, we need more. And so the second wave, Of course, we all know it's upon us. Here's the recruitment profile. You can see that at one point we restart were and, um, I've over 400 people per day. Uh, you can see that even doing this. The autumn we've been randomizing over 200 people some day and over 100 people for the last six weeks or so on earlier this week past 20,000 patients randomized in total. We're studying of age of new treatments, some of which we didn't know anything about before didn't even exist before. So aspirin it down on the bottom there because of the thrombotic complications that have have gained notoriety. But we didn't know that at the beginning. We know it now, so we'll study it. Cultures seen an anti inflammatory drug usually use the gout. Actually, I use it for a coupon card itis in some of my patients again Damn thing down the immune system. We know that the immune system is important because the dexamethasone results a new treatments Convalescent plasma, Regeneron's version of ah, monoclonal antibody. Target it despite protein now confidence in past. But of course, only starts to exist once you have some patients who are convalescing and secondly, devote the monoclonal spike antibody. Only when you've actually done the development work to actually develop that is the drugs and new treatments on Over on the right sauce a little map as an interleukin six antagonised trying to tackle those patients with the severe forms of Kobe my pocket here and and and information on just two on that Tosel is, um um, why do we need yet more evidence? Well, basically, because the position is not clear. There's a method Alice off a little existing trials that have actually announced results on mortality and given data you can see. Overall, that's what about 1400 patients. Also, 1200 patients randomized about 150 deaths. It's an uneven randomization 12% versus 10% on. In fact, what you you can see is that there's no rule effect on mortality now, each of those chances. Pretty small. It's all pretty inconclusive. We know remapped cap. It's safe. There's a 1.87 old ratio for better outcomes, which is a complicated scale, but we don't know how many deaths there are. We don't know how many of those patients were treated with the dexamethasone. We don't know what the scale of the improvement in mortality Marshall might not be. We knew more evidence, actually, in recovery. If you look in the middle there, we really have a lower 100 patients versus 1100 patients on. The topical is about comparison. The DMC happy for us to continue. That tells you one thing. This is not a slam dunk, but we also have the largest trials of many other treatments. Convalescent plasma used in 100,000 Americans. Were they the lucky ones or the ones that didn't get it? The lucky ones we don't know during the trial 3000 versus 3000 to date and climbing the monoclonal antibody is 700 versus 700 aspirin. As I say, I've gotten past the 1,001,000. The cultures seen only started about a week ago. Brain will the time is to get very clear answers clear answers might be. This treatment is works is we saw the dexamethasone. This treatment does not work. As we saw with Hydroxychloriquine. It might even be that this treatment is unsafe. We need clear answers on that's likely given the I come in to ventilate or mortality rate to require a least 2.5 1000 patients. That's it to other half 1000 patients. But we also have to bear in mind that the benefits might be restricted to a particular subgroup. So if you take convalescent plasma is an example, there's much more likely that will work in patients who have not or not yet managed to mountain there own antibody response. Then it will in people who have mounted an antibody response so it before we dismiss it is a completely ineffective treatment. We need to be clear, but we're not dismissing it on the basis are off a lack of statistical power. We need these big studies, the whole UK effort. So what opened the graph of the last shows is one bar 11 dot Perez and it just trust. Actually, this is just the English data rather the Scots and the well, sure that all that Irish but the pattern similar, pretty similar. You can see that some hospitals or some trusts have been incredibly busy and seeing huge numbers of patients. This is just in the last two months. Others have been quieter on the dot, So what you can see is that the proportion of patients recruited is very valuable on over average. One in 10 patients admitted to hospital with Kobe. It had gone into the child. That's impressive, but frankly, not good enough. If it had been one by patients, we would have the time to finding it. The answer is that we need on. What's interesting is the level of variability. There are some busy hospitals that have recruited, let's say, 25 or 30% of patients. There are some busy hospitals that have recruited, let's say, seven out of 1500 patients. Now. I think that that's not going to be down to differences in the local community. It's not going to be down to differences with individual doctors or sat o. R. Research nurses. It's much more likely to represent systematic issues with in particular hospitals. How does one prioritize the search? Mercy care? Actually, the chief medical offices at the beginning of the year said, there is no versus. Clinical trials are part of clinical care. That's what it means to tackle this this virus on on the right, I put a couple of quotes, which I really like. They were presented by local investigators. The recovery trial has inspired many more junior doctors in our trust to look again. It's a career in the search. It's given an opportunity and access to treatment to our patients. They otherwise would not have had that the bottom. We're pleased to take apart and contribute to a nephew that helped to provide clear answers. I talked about transparency, everything that I've said, actually with exception of the graft on the previous life. But everything else I have said is available on the public Web site. Every protocol, every ethics commission, every every chart, a submission, every bit of training material, every bit of patient facing material, any every result. That's no. All of that is on the on the public website, along with the overall recruitment on a live basis. It seemed to me they were expecting patients to take part in our trial. Why would we keep the protocol confidential? Mixing no sense at all. Why would it help? Why why can't we help others around the world also do trials by making a successful protocol open? Why would one hi to the recruitment numbers? Because somebody else might be thinking, You know, I might like to do a trial of cultures seen. Is it worth their while? Or we actually got to answer that question that they be better off setting something else. Openness is important on all levels. And so just to conclude, I thought I'd be useful to have er on American perspective. And so this is from The New York Times. It's one of my favorite articles of the year. They're they're a few of them, actually, but this is the favorites. I didn't like any of it or that was interviewed for it on. I said he didn't like the title. Where is America's groundbreaking at Covina? 19 Research. There's a new, awful lot to learn from Britain. What I like about it was it picked out eventually, six different areas where we really made a difference. It was designed to be easy to take part in. I told you that at the beginning. The key was we had to get the science right, but it had to be practical. The second is the protocol was quickly approved, and I was talking damage or a their annual meeting earlier on today and gave them enormous credit for that that so HR and others adopted vial hospitals across the country. The patient data has been a key feature drawing, so we have no lost to follow up. Leaders and government chief medical officers and others. Have I really driven trials are part of research and done that over and over again? Of course, the CR and the Clinical Research Network on. But I think really key has being that we have we have seen somewhat successful in saying, Actually, let's bring clinical trials to the bedside. Let's take the clinical trials to the patients. And instead, instead of expecting the patients to come in the clinical trials, the protocols written in a way that you do not need DCP training. You do not need to be a research nurse. You do not need to be professor or associate, clinical lecture or anything else every clinician can take part if they wish you with very brief but bread relevance training. Oops, If I just finish Sorry about this. I'm clearly incompetent when it comes to the technology. I think it's just helpful to look ahead and think What? What did we learn from all this? I mean, first of all, we're not out of coated Woods yet, so there's more to do. But the arm actually use an unproven treatments, really should be avoiding what has to ask for some very serious questions. Large randomized trials are critical component, not the only feature off. High quality clinical care and compelling results absolutely changed practice practice. But for that to happen, the trial must be feasible. It must be inclusive on it must be focused on what matters that does require leadership, requires coordination. It requires collaboration, a sense of fairness, admission for fairness on transparency. But as I say, that's not only relevant the co bit that's relevant for the burden of many other common diseases that have not gone away. Just because see, 19 has been on the front page is this year so very finally to thank? Obviously the funders, obviously the various partners, but enormous thanks to I think it's something in the region of 3.5 to 4000 doctors, nurses and pharmacists on the search stop at any chest hospitals across the country. Uh, we've endeavored to list of all in the supplementary appendices of all our publications, but in particular to the thousands of patients. 20,000 patients so far have taken part in the recovery trial. People are treating treated today better because of the contributions of patients who have attributed in the past. But in Covitz just to conclude, let's remember that we talk a lot about numbers. There's a sort of take it. Take track of across it at the top of every newspaper about the statistics of number of cases number, admissions, number of deaths it was up of. It is down the base. But remember that behind each one of those is a real person, really family, a really story on day over the course of the last nine months, roughly speaking, one in four patients who've gone into the hospital with significant co bit have ended up not making out of hospital life. That's why we do the Charles. It to find the treatments that work and use them. The ones that don't work in abandoned them, improve care and improve the care for individual patients. That families. I'm a public house. Thank you, Martin. Thank you so much. Good. You stop showing your screen. That be great. It's just brilliant to hear it straight from you. I you know, I love hearing it on the news and reading the papers, but to hear it from you as well just adds the whole extra nuanced interpretation of what's gone on. It's amazing. Thank you so much. We've got some questions on the chapter which I'm going to ask you on to start off with. I bet you've been asked this one, but you could ask them all before you've got literally hundreds of candidate drugs. Onda. How on earth you decide which one to enter in next. I wondered if you could maybe give us the story behind the coach has seen because that took us by surprise in Bristol. Yeah, sure. Um Well, um, at the beginning, I mean, first of all, we started this trial at risk. We didn't have a ground on. We decided we just get on and do it. There's an awful lot to be said for just getting on the doing things. Uh, the ground did actually turn out to arrive two days later. Um, fan of conditions. With that, some of the treatments would be included those those recommended by a committee called Nerve Tag, which actually Peter Chairs, which is a government advisory committee, suddenly feel like a just one step below, say, just one way of thinking about it, which had had done reviews of which treatments might be some pus treatments might be suitable. We in those early days we were picking treatments that have. Do you have some reason for thinking they work a known safety profile, enough drug that they we could actually do a decent sized trial on in particular enough drug, all the potential to get enough drugs You, enough people that if it turned out to be successful, it could be deployed as a population health treatment. So the fact that dexamethasone was this treatment that's in every pharmacy on could instantly be rolled out was no accident, which chosen treatments like now now, more recently over over the course of the summer, things have changed around a bit of a committee called the Cove It Therapeutics advisory panel was set up chair by Patrick Henry from the MRC and is essentially an independent group of advisors. Um, and remember from vessel hematologist was one of them. But there's people looking at somewhere embolism that antiviral so in the milk modulation and wanted to other things. We were reviewing through literally hundreds of suggestions that even open Web site where people could make their suggestions as well as a truly through the past literature. The cultures seemed specifically came up through the Immunomodulator e sort of subcommittee. It has known property is on the inflammacin in terms of dampening the immune system. Obviously, dexamethasone is also, if you like a general immune suppressant. Okay, we don't know that it's going to work. But what's been interesting is that although we all think of it is a gown treatment, um, Andi Well, think of it as being very limited by causing lots of diarrhea on not a treatment that we'd want, I think partly because none of us had actually won't get out, it's turned out that actually, in the last couple of years it's been used for acute per pericarditis and be trialed acute pericarditis and turn out. We use it for three months or more in in acute powered I pericarditis, sometimes without much in the way of side effects and with benefit proven benefit, I'm actually over the last six months or so. Perhaps it's slightly longer now, a couple of trials in acute or recent MRI, which have also suggested benefit big trials of 4000 people. Also. So this wasn't a treatment that was completely untested and just sort of popped out of the air. But on the other hand, how did it eat? Win over some other candidates will again. It's cheap, cheerful and available on when one thinks about a global pandemic, there's no awful lot to be said for that on. Do you know we've seen already that the the cost of the drug does not necessarily equate to the value of the drug? I'm fascinating. What's this space there every week in our A covert committee in Bristol when we know the results of next results about to come out? We have a sweepstake, Andre, wait to see what happens. We've been wrong every time. So, um we went to see another question Be wrong. Twice once is I've been running on what the drugs actually going to do. And and the second is that you don't being wrong on when the results are going to come out. I don't take any Texas of May. Um, next question. Um, it was obviously brilliant that dexamethasone was introduced into clinical practice really quickly and effectively. How could we learn to better disseminate results from trials immediately and get them taken up? What? What? What? What would you suggest? Well, I suppose it does depend on awful lot. On what? What? The balance is arm here. We had a condition with the one in for mortality on wear on a reduction in that mortality of a third. So it was a very big results on the ultimate outcome where there is no alternative on the drug where we knew the side effect profile. I mean, everybody lives at medical school. The side effects of steroids on particularly know don't lowest dose in short term, and everybody could deal with the hyperglycemia that might or might not occur from time to time. So that was one which was relatively easy to get into practice. And I think, um, they probably are some things we learn. We wouldn't have done it quite a fast. I think any of us if it is being a chronic condition. But it was very definitely the right thing to do. Yeah, we couldn't sit on those results for longer than about five days or whatever that we actually way didn't know, you know, I knew the answer for about five days before everybody else did. You can't sit on the result like that for any longer. And hence the press release and then the med are carbs. Quickly as we could on then the public. A preliminary publication and final publication come out soon. I think it would be a bit different of what we have been studying. Herds being entirely novel drug which required significant funding or which had a particular issues around safety profile or whatever, or where the games were less obvious. I need one looks at something like convalescent plasma. Um, then obviously, the challenge is not only once you've got the result, but how you're going to get enough of it was a really significant benefit. How you gonna get enough of it. And so the first challenge is going to be. How do you scale up if you like harvesting off a drug? How do scale production before we go down that route? So there are reasons why some things will be slower. But, I mean, I think there's a lot of things where, actually, what one's doing is studying two drugs that are widely known and widely used. And, you know, is my flavor of heparin better than your flavor of heparin. You take TEDs stockings worthwhile or not. You know, these are all the sort of questions which really could be rapidly implemented. But what often delay things is that the answers aren't clear. You have answers that people debate on. They start to look, then unpick the sub groups in the secondary outcomes, and they sort of you look at the data sideways and whatever else to either try and interpret. That's something definitely don't. There is a signal there, or there isn't a signal there according to their that that their their prior beliefs. Usually, if you get clear enough results, you will change practice because it's very clear. Of course I'll be extremes who will say always I told you so and they'll be people who said, I just don't believe it, But your sway, the vast majority of you get clearer results. Clear results. Not just the parts of regulating hurdle or a nice little or commissioning hurdle, but a guideline turtle on individual doctor and patient Hurdle. You've got to be looking a way to the end to the health benefits, not just the next step about Do I get it published or do I get Get a license? Thank you. And large trials help get clear results. Lizzie's waving at hand. There's a little you talking, you know you're not talking to me. No, Sorry. Next question. There's a few questions on the chat about the governance and the ethical processes that will obviously simplified recovery. And how on earth do we maintain that? Beyond the pandemic? Yeah, I Yeah, I mean, huge credit to all involved, particularly in the early days on D. Um you know, we went from protocol. Yeah, written on the 10th, also on Do approved within about a week. That's not sustainable. You know, A lot of people did not sleep, including the regulators and the ethics committees and everybody else did not sleep for weeks and a week, weeks on end during that during that phase, one cannot continue in that. In that way, it's not healthy. One will never recruit another regulated, if that's what it means. So I think that the um but I do think what one of the first thing I noticed was, when you empower people to say yes as opposed to do the delay, ask more questions, refer back or referred onto the next committee. It's amazing how people are perfectly capable of making sound reasons. Decisions on it's not clear that those decisions would be any better if you've gone through all the rest of the elaborate processes, nothing. We didn't skip any steps. We were challenged. There were things were asked to change or things. We had to have dialogue with the material that it's committing forever. But a lot of time people were thinking, How can we make this work as opposed to somehow? Trials of risky clinical care is risky, particularly clinical bearing. The absence of evidence is risky, so the question is every little burden that you put in the way is it really justified that delegation of duties. No, I mean why? I mean, if you have a allegations of duties, love. When you are consultants surgeon, you have a team of surgeons with Junior. It's it's tough with you if you run award a zoo. A nursing sisters. Do you have a set of delegations? You have training mechanisms in place. You have support mechanisms. You have mentorship. That's part of what these organizations have. Why do you then need to suddenly document everything in delegation of duties? Locks just because you're prescribing something by the cost of sorts of a coin? Another way to prescribe something for half the patients, as opposed to prescribing something with their no ability to learn to allow the patients? It makes no sense. Yes, I really hope that's the case. And just another couple of present. I think we'll write for time. We're allowed to use up the coffee shop Time I come in, I asked. I was on mute. Classically, everybody had at least has been only once during every one of these of afraid of long drink, just on your point that you just mentioned. So you lose you to that at your your critical or on my marriage air I/O, you have very easily see even with well, and they're very streamline. When you mentioned that you've really cut out, made it very clear of the information for patients. Do you think this is something that we can carry forward, especially in things like drug trials? Yeah, I think it's It's something you have to carry forward. I mean, you the take dexamethasone we didn't need to study for, you know, adverse events and even the serious adverse event that, notwithstanding the fact that patient admitted with Kobe, it online to you is essentially one infinite Siris of adverse events happening second by second. And it's only question, Which one do you write down? I mean, that doesn't make any sense either, but we know that we know the safety profile. We know a lot about dexamethasone. The only thing we didn't know what it does. It saves lives in Khost bit. So that's essentially, you know, quite. But that's the thing that you focus on. It's different with other drugs. You may not know so much, but you don't have to learn everything in one in every trial, so if you take the Regeneron's monoclonal antibody, which is unlicensed, actually has now has any weight for outpatient using that in the states. We don't know the full safety profile of clouds. But again, the purpose of the recovery trial is to understand that it saves lives. There are other Phase two phase three trials, which is much, much smaller because they know they're going to give the study mortality. But what you're collecting information on on both events or serious adverse events on Even in recovery, we have added a particular targeted questions, particularly to work to work out whether there's the equivalent of transfusion type reaction. So as the infusion goes in, does somebody get another anaphylactic type reaction? The BP drop on on some of the soap? Or so you got targeted questions that something which we do want to know about. We don't need to know everything in every trial. And, you know, there wasn't a previous on protocol for this. We didn't take a a child units or sponsors or something. 10 year prefilled template to write this. We started out by saying what we need for this trial so you won't find the page is a standard definition is that don't make any sense of adverse events and what's related and what's not. It's not in that because it's not relevant. So you very much focused, I guess. If I yeah, I the pieces of protocol on Most Proud off I think it is worth having a look at the sort of quality vitals on type pages approached the marching them approach to training type pages because they were very deliberately written thinking. Well, we know there's these requirements. We know there's a GC three principal. We're not trying to break those, but let's have a sound reasoning to justify or explain what I provide the rationale for what we are doing. So there's only a couple of pages. It's not written in the sort of language you're seeing in in most protocols, but I think he's very useful at the sort of model. Do not copy and paste it, that is, that's the whole point. Take it, think about it and apply it that the principals to your own trial, because that's actually how you drive up the quality. Oh, you know, I think those that those were this is a bit high as I was writing it. In some ways, I enjoyed writing the notes. I mean, yeah, it's been under my God, It's got outcomes. It's got a meeting criteria. I mean, yeah, but those are the best. I guess I enjoy writing the most. I'm going to start worrying about you, Martin. Two more quick questions. So I think training, involvement in recovery and trainee involved in Covitz said. Which is the other projects? That's Bean on tonight. Both of you could answer that one. It's a how you doing in recovery or have you did it? In fact, we can talk a little bit about the cable service training involvement that sounds with many of their sort of national research cognitive projects. This, this training involvement every level really embedded within the group. So within the course steering group, the dissemination committing that there's a medical student in Morocco that's done a just a wonderful job of getting hundreds of hospitals involved in in study training is involved in the in the preschool phase, and I think it's it's many of the lessons that you share with this this evening. Martin. Everything is very streamlined, simple, you know got short. CRF Such a short protocol was with three pages. I know it's not a trial political, but we did our best On the front page is just a letter to invite people Teo to get involved with. That should shorts protocol we've ever seen involved. Then I think it's all about creating a culture around training involved in in research. And I really liked your reflection from one of your local chief. Investigate. Sorry, principal investigators about how they've seen this powerful research, you know, getting people excited about the research process. And I think a Zagreb and we should absolutely be encouraging that wherever possible. And this is your job. You have any reflections from dissemination committee perspective? Yeah, definitely. As as you said, trainings played a very important role, and actually, they teach to us how they've taught us how to disseminate the results all over the globe with different strategies in different countries. So, for instance, we have to train is leading Brazil, and their strategies is, for instance, to translate. It's every piece of text we need to to communicate to the collaborators there, and then and and then obviously we have the visual abstracts of each paper with published, and they also want to translate them in their their native languages. And then we've been really learning from the trainees because they're very close to the surgical community, and they're very close to what we can actually change in clinical practice. And then trainings have been a huge work force behind not only setting up the study but also disseminating the results in a very efficient way that can actually change practice. And Martin, you got resource it dry skin now in recovery, which is only two, apparently 70 have signed up. 70 have signed up already, which is fantastic. But I mean all the way through. And if you look at the protocol, it even talked about medical students on declare call staff and on go on, being part of the trial, you could use you to the child. Uh, my son's house make was, uh, his first six months job, or perhaps a second six months job. A Suhas hman on do his name's on the paper, you know, because he was what he drawing or somewhere contributed to the way that the trial work there. It gives experience that actually research is not something in transit, not something that had done by special people on that done elsewhere. They've done here and now as part of the clinical care. And that's so important. So we have to make it easy for that to happen, given a little bands on those people. But that was very much part of the intention. I am delighted to see 1st 100 that in your urine in general of medicine, paper. You know, it's just a single corporate Ortho group, and we sort of live in died by that as well. And I think it's such a positive way of engaging people across a little training stages to make them everyone feel like that they're part of something bigger. Perhaps so, yeah, I think that's a great model for evidence to consider using into the future. One last question. Not in the, um, your 28 more than 28 days or 20 clearly, really important to you, and you're going to link it to the state of the long time out or whatever. Whichever date is that is to get the long term outcomes in terms of long term survival, When will we be hearing those results roughly. Well, uh, we re annoyance the dexamethasone results in mid June. So we're just about at six month follow up for the for the fight for the final patients. Perhaps not quite because some patients were still in the child, just we we sort of close it to enrollment. So my guess is that six months will be up for everybody in January, and then we have the challenge of writing that up. I have to say that the writing up is one of the biggest challenges because the papers have come so they can fast on. We're doing your pre Prince pressure leases, preliminary publications, final publications on being with the the rounds and rounds with reviewers and so on, Um on it's entirely possible that other results will come up, but, you know, six months will be up in January that soon as we can do it. After that, we will think there's not. There's not inconsiderate. There are considerable data management's challenges in a lot of well, and that's been it usually only care, but I think we'll be useful to talk to all of us in the future. Thank you. I'm gonna have to shut up because we've gone over time. But thank you so much. Again. To Martin and to James and Joe and Lizzie. Thank you. I'm gonna hand back to the take, Emily, who's gonna close it, and then we'll finish. Thank you. No. Well, thank you all so much for this excellent session. It's been a real privilege to be able to learn from all of your experience It