WEBVTT NOTE This file was generated by Descript 00:00:00.029 --> 00:00:03.339 Judith: Welcome to Berry's In the Interim podcast, where we explore the 00:00:03.339 --> 00:00:07.829 cutting edge of innovative clinical trial design for the pharmaceutical and 00:00:07.829 --> 00:00:10.199 medical industries, and so much more. 00:00:10.779 --> 00:00:11.500 Let's dive in. 00:00:12.487 --> 00:00:15.327 Scott: Welcome everybody back to In The Interim. 00:00:16.067 --> 00:00:23.907 I'm your host, Scott Berry, and I've got a, a, a wonderful topic today and I was, I 00:00:24.007 --> 00:00:30.427 was chatting with Steve just before we hit go here on, th- we're episode, I believe 00:00:30.507 --> 00:00:37.027 episode 65 of In The Interim, and I think, uh, at, you know, spending t- I've 00:00:37.067 --> 00:00:39.797 been doing clinical trials for 27 years. 00:00:40.187 --> 00:00:43.687 If I were to stop tomorrow and somebody said, "Scott, what was 00:00:43.746 --> 00:00:45.767 your biggest accomplishment?" 00:00:46.567 --> 00:00:48.147 It would be Remap-Cap. 00:00:48.867 --> 00:00:53.747 Remap-Cap to me will be, you know, one of the incredible things in 00:00:53.787 --> 00:00:55.767 my life, the experience of it. 00:00:56.427 --> 00:01:01.647 It in of itself as a scientific beast, the impact it's had, the, 00:01:01.867 --> 00:01:05.406 the so many aspects of it, the friendships that have grown out of it. 00:01:05.687 --> 00:01:10.027 So it's, it's the most impactful and here we are, episode 65, and this is the 00:01:10.147 --> 00:01:12.527 first episode on the Remap-Cap trial. 00:01:13.407 --> 00:01:17.487 Part of it is it's such a beast to get your arms around. 00:01:18.007 --> 00:01:21.027 So I, I'll introduce and we'll, we'll talk about this. 00:01:21.107 --> 00:01:25.087 This is going to be the origins of the Remap-Cap trial. 00:01:25.207 --> 00:01:30.207 In and of itself is such a cool story of it, and my guest today 00:01:30.787 --> 00:01:33.747 was there, creation of this. 00:01:34.327 --> 00:01:38.767 Also a very good friend, uh, uh, of mine, Steve Webb. 00:01:38.867 --> 00:01:44.907 Steve is a professor, uh, is intensive care specialist and 00:01:44.967 --> 00:01:48.887 a professor of critical care research at Monash University. 00:01:49.347 --> 00:01:52.647 He's also the executive director of Empiric, which 00:01:52.667 --> 00:01:54.287 is a whole separate podcast. 00:01:55.067 --> 00:01:59.647 Uh, interestingly, you know I do a lot of sports things and, and in sports they 00:01:59.727 --> 00:02:01.947 talk about a first ballot Hall of Famer. 00:02:02.627 --> 00:02:07.427 Steve, in 2014, the Australian government estabuli- established the 00:02:07.467 --> 00:02:13.267 Australian Academy of Health and Medical Sciences, and he was part of the 14 00:02:13.387 --> 00:02:15.407 fellows that initiated the academy. 00:02:16.147 --> 00:02:18.587 So very well-respected researcher. 00:02:19.047 --> 00:02:23.837 He's, his clinical trials he's designed have enrolled more than 70,000 00:02:23.987 --> 00:02:29.467 patients, 200 million in funding, more than 30 papers in The New England 00:02:29.567 --> 00:02:35.907 Journal and JAMA, more than 75,000 references, huge impact on patients. 00:02:36.327 --> 00:02:41.967 He's also one of the global leaders of the Remap-Cap platform trial and was 00:02:42.047 --> 00:02:47.967 the head of the International Trial Steering Committee when COVID hit, and 00:02:48.027 --> 00:02:49.987 that'll be a big part of our story. 00:02:50.047 --> 00:02:52.267 So Steve, welcome to In The Interim 00:02:53.652 --> 00:02:54.933 Steve Webb: Thank you very much, Scott. 00:02:54.972 --> 00:02:58.672 It's a, pleasure to be chatting about The Beast 00:02:59.866 --> 00:03:01.166 Scott: Yes, the beast. 00:03:01.786 --> 00:03:02.426 All right. 00:03:02.586 --> 00:03:07.506 So I was curious going back and, and remembering this, and I got in a bit of 00:03:07.606 --> 00:03:12.906 a, of, of a rabbit hole, uh, with this and looking back at all the emails. 00:03:12.966 --> 00:03:15.346 I wanna know, when was the first email… 00:03:15.687 --> 00:03:18.886 I have all my emails ever from Berry Consultants, which is, is 00:03:19.027 --> 00:03:20.767 fun, fun things going back to. 00:03:21.226 --> 00:03:25.267 The first email that ever showed up with Steve Webb on it. 00:03:25.966 --> 00:03:34.066 So I look back, and this was, uh, March 13th, 2012, is the first email 00:03:34.127 --> 00:03:38.806 where you and I are both on the email, and it's from Derek Angus. 00:03:39.107 --> 00:03:44.206 It's a follow-up to a Pittsburgh meeting that is talking 00:03:44.426 --> 00:03:47.746 about potential p- pandemic. 00:03:47.926 --> 00:03:52.806 Sorry, I wasn't there, but, uh, the aftermath of this came about. 00:03:53.206 --> 00:03:59.666 Do you wanna describe this meeting and the subsequent meetings and pandemics? 00:04:01.181 --> 00:04:06.981 Steve Webb: So the story of Remap Cap really starts in the southern hemisphere 00:04:07.141 --> 00:04:14.291 winter of 2009, when the swine flu pandemic, uh, spread around the world. 00:04:15.201 --> 00:04:20.201 to Australia, New Zealand, other parts of the southern hemisphere, uh, first, 00:04:20.261 --> 00:04:22.501 and it, it was a decent pandemic. 00:04:22.781 --> 00:04:27.321 Um, uh, in the Royal Perth Intensive Care Unit, where I was a, a specialist, 00:04:28.371 --> 00:04:32.141 uh, at the peak of the pandemic, half of the intensive care unit 00:04:32.221 --> 00:04:36.081 was occupied by patients with swine flu, all of whom were ventilated, 00:04:36.461 --> 00:04:38.301 all of whom, uh, were very sick. 00:04:39.371 --> 00:04:46.061 Um, but, uh, swine flu, um, came and went, um, uh, uh, over the space, uh, of two 00:04:46.141 --> 00:04:48.041 winters, one southern, one, one northern. 00:04:48.921 --> 00:04:55.641 And, uh, um, the world sort of, um, took a breath and said, "Well, that was bad, 00:04:55.721 --> 00:04:58.081 but it could have been a lot worse." 00:04:58.141 --> 00:05:01.461 And so a bunch of people got together from the intensive care world to 00:05:01.541 --> 00:05:06.140 think about how could we be better prepared for future pandemics. 00:05:06.941 --> 00:05:13.861 Um, in Australia, New Zealand, uh, we did some observational, um, uh, work, which 00:05:13.961 --> 00:05:18.761 was, uh, quite valuable from a public health perspective, we had no chance 00:05:18.801 --> 00:05:23.161 of putting together a clinical trial in the time span that was available. 00:05:23.341 --> 00:05:27.901 A wave would hit, it would last about eight weeks, um, and you just can't launch 00:05:27.911 --> 00:05:34.481 trials, um, uh, at least, uh, at that time, over that sort of, uh, timeframe. 00:05:35.261 --> 00:05:41.751 was a, a meeting in 2010 in Toronto, uh, where Derek Angus, uh, who was 00:05:41.781 --> 00:05:46.621 also, uh, um, one of the, um, together with you, me, and Roger, probably 00:05:46.641 --> 00:05:48.661 the midwives, uh, of this thing. 00:05:49.561 --> 00:05:52.221 Um, and your dad spoke at it, Scott. 00:05:52.721 --> 00:05:52.961 Um, 00:05:53.062 --> 00:05:53.222 Scott: Yep. 00:05:53.663 --> 00:05:53.783 Yep 00:05:54.301 --> 00:05:59.761 Steve Webb: talked about adaptive platform trial methods, and it made a lot of sense. 00:06:00.241 --> 00:06:04.401 Although I've got to say, I had to listen to talks from Don, from you, 00:06:04.781 --> 00:06:10.721 from Roger, at least six times before I, um, finally thought, "I-- Now 00:06:10.861 --> 00:06:14.921 I understand this, uh, this thing called an adaptive platform trial." 00:06:15.841 --> 00:06:19.821 Um, and then the 2012 meeting that you referred to was in Pittsburgh, 00:06:19.871 --> 00:06:23.001 and Roger, uh, Roger Lewis was there. 00:06:23.701 --> 00:06:29.821 Um, and, um, uh, that was really, a series of meetings about, you know, nine 00:06:29.861 --> 00:06:37.221 months apart, we decided that adaptive platform trials were the only thing 00:06:37.230 --> 00:06:40.421 that made sense for future pandemics. 00:06:40.461 --> 00:06:48.741 Because they create, um, um, warm infrastructure can pivot and adapt rapidly 00:06:48.801 --> 00:06:53.331 to whatever is needed for a disease that can't be predicted in advance. 00:06:56.122 --> 00:06:59.222 Scott: Uh, that, that, that I think comes to fruition. 00:06:59.822 --> 00:07:04.202 So there's these d- lots of researchers meeting, ISARIC. 00:07:04.642 --> 00:07:07.682 Uh, John Marshall was at a number of these meetings, who ends up 00:07:07.722 --> 00:07:11.023 being a, a, a, a very important player in the REMAP-CAP story. 00:07:11.523 --> 00:07:13.122 And I, I think my… 00:07:13.203 --> 00:07:18.642 I enter this in, uh, on July 2nd, 2012. 00:07:18.722 --> 00:07:21.682 There's an ISARIC meeting in Annecy, France. 00:07:21.742 --> 00:07:22.882 I believe you were there. 00:07:23.662 --> 00:07:23.842 Yeah. 00:07:24.082 --> 00:07:27.443 So I believe it's probably the first time we met, uh, in that, 00:07:27.762 --> 00:07:32.622 and I presented on adaptive trials, and it was the first sort of what 00:07:32.682 --> 00:07:34.642 could this look like in a pandemic. 00:07:35.063 --> 00:07:40.962 There was a two-day working group from that, and I think from that largely 00:07:41.142 --> 00:07:43.662 grew the pr- grew the PREPARE network 00:07:44.916 --> 00:07:45.716 Steve Webb: Co-correct. 00:07:46.736 --> 00:07:54.496 Herman Goossens, uh, was a, um, very, um, inspirational and influential infectious 00:07:54.556 --> 00:07:56.776 diseases physician based in Belgium. 00:07:58.056 --> 00:08:03.036 uh, he understood the damage that pandemics could, uh, do to the world if 00:08:03.116 --> 00:08:09.136 one turned up, and the critical need of being able to generate evidence rapidly 00:08:09.257 --> 00:08:14.916 about, uh, um, optimal treatment in a situation where, um, the clinical 00:08:14.996 --> 00:08:19.816 trial, uh, design and infrastructure needs to be constructed, um, in the 00:08:19.877 --> 00:08:22.036 presence of enormous uncertainty. 00:08:22.916 --> 00:08:29.756 And so Herman, uh, um, uh, um, uh, proposed, uh, to the European Union 00:08:30.476 --> 00:08:36.556 that there would be a funding call for a consortium around pandemic preparedness. 00:08:36.956 --> 00:08:39.296 And it was a fantastic program of work. 00:08:39.337 --> 00:08:41.036 There was lots of laboratory science. 00:08:41.056 --> 00:08:43.636 There was stuff about, uh, diagnostics. 00:08:43.677 --> 00:08:47.596 There was stuff about consumer and community engagement, about how you 00:08:47.636 --> 00:08:51.616 prepare the community for a future pandemic in terms of the research that 00:08:51.676 --> 00:08:54.296 needs to be, uh, conducted at the time. 00:08:54.337 --> 00:08:58.176 And one of the work packages, uh, work package five, as I recall, 00:08:58.676 --> 00:09:04.896 was an adaptive platform trial, uh, for, um, any future, uh, pandemic 00:09:07.034 --> 00:09:07.555 Scott: Uh, yep. 00:09:07.974 --> 00:09:13.594 Uh, and, and that's sort of where, where I, I sort of really remember starting 00:09:13.674 --> 00:09:15.534 on this, and it was called Prepare. 00:09:15.594 --> 00:09:18.995 And we were talking about at the time, I think we were talking 00:09:19.074 --> 00:09:21.995 about a platform for antibiotics. 00:09:22.414 --> 00:09:29.514 It, it was relatively generic treatment, but we, we hadn't jumped into the, 00:09:29.594 --> 00:09:35.174 the, the multifactorial, the huge aspect, which is really interesting 00:09:35.234 --> 00:09:39.254 part of the pandemic was the abil- was the factor- multifactorial story 00:09:39.275 --> 00:09:40.714 of that, but we'll get to that. 00:09:40.754 --> 00:09:40.935 But it 00:09:41.005 --> 00:09:41.415 Steve Webb: Yeah, no, I, 00:09:41.445 --> 00:09:41.575 think, 00:09:42.135 --> 00:09:42.435 Scott: it was… 00:09:42.545 --> 00:09:42.825 Steve Webb: I, I 00:09:42.935 --> 00:09:43.034 Scott: Yeah 00:09:43.405 --> 00:09:47.145 Steve Webb: I think it, I think it was multifactorial from the get-go. 00:09:47.165 --> 00:09:53.765 But part of, um, uh, the discussion and the concept at the time that the only way 00:09:53.845 --> 00:10:00.755 to be ready for a, a, a pandemic was to have that were already recruiting to other 00:10:00.805 --> 00:10:05.555 questions that were-- that are relevant, uh, to improving patient outcomes. 00:10:06.795 --> 00:10:11.085 and so part of the concept was to construct this, uh, platform that 00:10:11.165 --> 00:10:16.404 would, uh, do good things, uh, during the inter-pandemic, uh, period. 00:10:16.785 --> 00:10:21.545 And, uh, um, patients with pandemic influenza, or as it turned out, pandemic 00:10:21.605 --> 00:10:27.845 COVID, have, um, essentially a diagnosis of severe acute respiratory illness 00:10:27.885 --> 00:10:29.585 or community-acquired pneumonia. 00:10:30.385 --> 00:10:34.525 so the plan was to construct a platform that would recruit patients, uh, with 00:10:34.585 --> 00:10:39.565 community-acquired pneumonia, ask questions that were relevant to improving, 00:10:39.965 --> 00:10:45.305 uh, patient outcomes, because CAP is a, um, a major driver of, um, um, uh, 00:10:45.425 --> 00:10:51.025 bad outcomes, um, and be able to pivot, uh, when a pandemic, uh, turned up. 00:10:51.725 --> 00:10:58.525 So having succeeded in getting that grant call, uh, included within, um, what was 00:10:58.585 --> 00:11:04.864 then the, uh, FP7 scheme, subsequently has become the Horizon, uh, scheme. 00:11:06.115 --> 00:11:12.705 Um, the, um, uh, um, put together a really impressive, uh, uh, consortia. 00:11:12.865 --> 00:11:17.905 Um, uh, Derek, myself, you, all contributed to, uh, the design 00:11:17.965 --> 00:11:21.745 of what was included within work package fee-- uh, work package five. 00:11:22.645 --> 00:11:22.755 it 00:11:22.878 --> 00:11:23.058 Scott: And 00:11:23.305 --> 00:11:25.185 Steve Webb: uh, I don't know, it was maybe a page and a half 00:11:25.225 --> 00:11:27.385 in this, uh, massive grant 00:11:27.451 --> 00:11:27.670 Scott: Yeah. 00:11:28.965 --> 00:11:32.565 Steve Webb: And, um, uh, after the wheels turned inside the 00:11:32.605 --> 00:11:36.425 European Union, e- I can't even remember exactly what year is it. 00:11:36.505 --> 00:11:38.935 Might have been 2015 or 2016 now. 00:11:39.765 --> 00:11:43.825 grant is, uh, successful, and we're away 00:11:45.219 --> 00:11:50.438 Scott: Yeah, and interestingly, as part of this story, the federation of this, 00:11:50.518 --> 00:11:57.198 this trial grows into something that has multiple sponsors globally and a single, 00:11:57.758 --> 00:12:03.078 uh, platform that, that has the federated, and we, we talk a little bit about that. 00:12:03.518 --> 00:12:09.578 But I found an email in December of 2013 where you send out that you 00:12:09.638 --> 00:12:17.958 now have funding from the NHMRC, uh, to extend this to Australia 00:12:18.038 --> 00:12:19.378 and, and what this would look like. 00:12:19.398 --> 00:12:23.778 And this starts a little bit the federation of what becomes Remap-Cap 00:12:25.205 --> 00:12:25.485 Steve Webb: Yeah. 00:12:25.545 --> 00:12:31.165 So that money was largely used to, um, uh, pay for the preliminary work 00:12:31.205 --> 00:12:37.425 that was necessary to write a grant application to the NHMRC, uh, for what 00:12:37.465 --> 00:12:40.225 was called various things back then. 00:12:40.445 --> 00:12:43.785 Uh, it was-- Once upon a time, it was GACSARI, then it was ADCAP, 00:12:43.825 --> 00:12:45.895 and, uh, then it was OPTIMIZE-CAP. 00:12:46.805 --> 00:12:51.785 but that NHMRC grant application, uh, uh, was, was successful. 00:12:51.805 --> 00:12:57.744 And the preceding FP7 grant, I think, made a massive difference to the likelihood of 00:12:57.865 --> 00:13:02.325 success of the Australian grant because it had already been through peer review 00:13:02.425 --> 00:13:07.025 in another location, though it was a relatively small part of this big, massive 00:13:07.105 --> 00:13:09.585 pandemic, uh, preparedness consortia. 00:13:09.945 --> 00:13:12.945 But that gave it credibility, and I think that likely helped, 00:13:13.065 --> 00:13:14.305 uh, get it over the line. 00:13:14.765 --> 00:13:19.245 So that had us funded in two countries, in, in two regions. 00:13:20.085 --> 00:13:20.385 And 00:13:20.465 --> 00:13:24.885 next to come on board was John Marshall, who somewhere through that time period 00:13:24.945 --> 00:13:30.805 was successful at getting, uh, it funded, uh, through the CIHR in Canada. 00:13:31.625 --> 00:13:36.445 And, um, really with Derek's intercession, um, we settled 00:13:36.485 --> 00:13:38.725 on the name of, uh, REMAP-CAP. 00:13:39.145 --> 00:13:44.065 Uh, uh, De-Derek had had a, um, uh, a viewpoint article in JAMA through 00:13:44.145 --> 00:13:50.385 that area-- through that era, he had, um, proposed the term REMAP 00:13:50.395 --> 00:13:54.825 to describe, uh, you know, the, the generic description of the beast. 00:13:55.245 --> 00:13:57.225 A randomized embedded 00:13:59.445 --> 00:14:01.615 adaptive, uh, platform trial. 00:14:01.925 --> 00:14:06.725 And of course, it was also remapping the way that clinical trial evidence, 00:14:06.865 --> 00:14:09.015 uh, should be, uh, should be generated. 00:14:09.425 --> 00:14:12.635 Uh, uh, Derek's, uh, uh, well, he's, he's got-- Uh, uh, 00:14:12.635 --> 00:14:12.715 Scott: Yeah. 00:14:13.185 --> 00:14:15.675 Steve Webb: Derek's, Derek's not short of marketing ability, 00:14:15.705 --> 00:14:17.065 and it matches his substance. 00:14:18.375 --> 00:14:21.175 Scott: Yeah, yeah, and a, and a fabulous name. 00:14:21.615 --> 00:14:23.675 So a little bit, you touched on this a little bit. 00:14:23.755 --> 00:14:27.055 Let's, let's talk about the sort of scientific structure of this thing 00:14:27.095 --> 00:14:31.095 that was created, which started enrolling patients, I believe, in 2015. 00:14:31.695 --> 00:14:33.595 The first patient was enrolled in this. 00:14:34.615 --> 00:14:38.515 Uh, uh, so it was '15 or '16, it was relatively early. 00:14:39.035 --> 00:14:44.804 Uh, it-- we, we weren't, we didn't have a super mature protocol, and we'll get into 00:14:44.804 --> 00:14:51.195 the, the development of what I think is a Tolkien-esque document in and of itself. 00:14:51.235 --> 00:14:57.315 But the Prepare solution, you talked about this, was to start a standing 00:14:57.775 --> 00:15:03.285 master protocol where in the back, in the backdrop to this, we called 00:15:03.335 --> 00:15:07.715 it a sleeping strata, we would talk about a potential pandemic. 00:15:07.795 --> 00:15:13.135 So if there was a swine flu, if there was Pandemic X, we 00:15:13.195 --> 00:15:15.235 could immediately pivot to that. 00:15:15.835 --> 00:15:20.995 But meanwhile, there's a t- a trial going on, and I believe the first, 00:15:21.755 --> 00:15:27.335 the first therapies being w- used were five different antibiotics 00:15:28.395 --> 00:15:31.975 as an antibiotic strategy, so a patient could be randomized to that. 00:15:32.795 --> 00:15:38.635 A question of extending macrolide to four days or 10 days, so that was a 00:15:38.795 --> 00:15:43.395 second question that a patient could be randomized at in a factorial way, as 00:15:43.455 --> 00:15:45.505 long as the antibiotic had macrolide. 00:15:46.155 --> 00:15:53.775 Uh, and then was this strange beast, hydrocortisone, um, uh, which I, I'm so 00:15:53.935 --> 00:15:59.155 fascinated by corticosteroids and do they work, do they not work, uh, question. 00:15:59.235 --> 00:16:03.485 But, uh, patient-- the question was should you give patients steroids, 00:16:04.135 --> 00:16:06.935 uh, uh, severe patients, uh, in these? 00:16:07.295 --> 00:16:11.575 Originally, I believe this was somewhat severe patients. 00:16:11.735 --> 00:16:17.605 This was ICU-based severe patients, and these were the three questions that 00:16:17.635 --> 00:16:23.735 were enrolling at the launch of this Prepare trial that migrated in name 00:16:23.795 --> 00:16:26.735 to Remap-Cap in a factorial experiment 00:16:28.125 --> 00:16:32.885 Steve Webb: There was an initial protocol, um, which, um, to the 00:16:32.925 --> 00:16:36.985 best of my recollection, uh, did get us, uh, recruiting in a small 00:16:37.065 --> 00:16:40.885 number of locations that didn't include Australia at that stage. 00:16:41.385 --> 00:16:46.605 But I think it was apparent that, um, the protocol that had been written 00:16:46.645 --> 00:16:54.905 initially was, um, um, w-was a standalone master protocol containing everything. 00:16:56.365 --> 00:17:03.005 uh, if one looked as to how this is going to evolve, adapt, new questions coming 00:17:03.085 --> 00:17:09.865 in, um, there was a feeling that this sort of, um, single protocol document wasn't 00:17:09.905 --> 00:17:13.385 going to be, uh, effective over time. 00:17:13.405 --> 00:17:19.805 And that led us to the development of the modular protocol, which, uh, we've used, 00:17:20.245 --> 00:17:22.725 I think, quite successfully ever since. 00:17:22.745 --> 00:17:28.905 And the principle here is to have a core or master protocol that contains 00:17:28.945 --> 00:17:35.125 the eligibility criteria at platform level and the primary endpoint that's 00:17:35.145 --> 00:17:40.145 going to be used at platform level across, uh, all of, uh, the domains. 00:17:40.605 --> 00:17:43.865 Little bit about the disease of interest in terms of background. 00:17:44.245 --> 00:17:48.825 Quite a bit about the statistical methods that are going to be used 00:17:48.885 --> 00:17:53.125 in the platform, there's a separate statistical analysis appendix. 00:17:53.715 --> 00:17:58.385 But nothing about the, uh, interventions that are going to be 00:17:58.425 --> 00:18:00.825 evaluated, uh, within the platform. 00:18:01.485 --> 00:18:03.845 So we had to invent a word. 00:18:04.065 --> 00:18:09.485 We invented the word domain to describe sets of mutually exclusive, 00:18:09.705 --> 00:18:14.885 uh, interventions that would be, um, uh, represent the, um, 00:18:14.925 --> 00:18:21.805 comparisons that, uh, existed, around specific, uh, um, modes of therapy. 00:18:22.625 --> 00:18:27.885 And the protocol has this structure of a master protocol onto which are 00:18:28.065 --> 00:18:34.385 bolted, multiple domain-specific appendices, and they contain the 00:18:34.425 --> 00:18:38.384 information about, uh, the background information about why that's a relevant 00:18:38.485 --> 00:18:42.585 question and the, uh, appropriateness of the interventions and what's known. 00:18:44.525 --> 00:18:51.565 domain-specific eligibility, uh, criteria, appropriate, domain-specific secondary 00:18:51.645 --> 00:18:58.045 endpoints, my favorite section of every REMAP-CAP protocol, the statistical, uh, 00:18:58.125 --> 00:19:03.954 approach to this particular domain, which is like selecting from a menu that is 00:19:04.005 --> 00:19:09.485 set out in the master protocol, in the core protocol, about what statistical 00:19:09.485 --> 00:19:15.785 triggers, what combination of states and strata apply to, uh, the, to this domain. 00:19:16.808 --> 00:19:22.788 Um, so, um, uh, that modular protocol structure I think has been a critically 00:19:22.868 --> 00:19:28.288 important part of the success of REMAP-CAP, it was a substantial advance, 00:19:28.709 --> 00:19:33.549 and it proved its worth in the pandemic, where with this modular structure, 00:19:34.368 --> 00:19:38.908 could write a new domain-specific appendix, do the associated data 00:19:38.969 --> 00:19:43.249 management changes, and have a new domain running in three or four weeks 00:19:45.051 --> 00:19:49.431 Scott: Yeah, I'm, yeah, so, uh, it, we- we'll get to the pandemic, but 00:19:49.531 --> 00:19:54.331 I agree with you that the previous document wasn't ready for that. 00:19:54.851 --> 00:19:58.951 And I remember we had this sequence, there were a number of players involved. 00:19:58.991 --> 00:20:02.691 Colin McArthur was involved, Alastair w- was involved. 00:20:02.731 --> 00:20:07.891 But it was a sequence of about a, a three weeks to a month 00:20:07.931 --> 00:20:11.121 where you, Derek, and I were… 00:20:11.151 --> 00:20:14.611 It was morning in the US, it was your evening. 00:20:14.651 --> 00:20:18.631 Derek and I would have coffee, and you would have a glass of wine next 00:20:18.671 --> 00:20:20.091 to you, and we'd be working on it. 00:20:20.671 --> 00:20:24.751 The- then all of a sudden, you'd wake up the next morning, and it would be night, 00:20:24.791 --> 00:20:28.891 and Derek has a nice big, uh, glass of wine, and you've got your coffee. 00:20:28.951 --> 00:20:32.941 And it was morning and night, and morning and night writing this. 00:20:32.971 --> 00:20:36.391 And I refer to it almost as Tolkien-esque because Tolkien, when 00:20:36.411 --> 00:20:40.631 he wrote The Lord of the Rings and all this, he invented languages for 00:20:40.731 --> 00:20:46.471 the Elvish, he invented songs, and we had to invent all this terminology. 00:20:46.551 --> 00:20:49.970 What, what works for this description of a common set of 00:20:50.011 --> 00:20:51.641 interventions being compared? 00:20:52.351 --> 00:20:57.231 And you can't reuse a word that means something else in clinical trials because 00:20:57.271 --> 00:20:59.331 then everybody confuses what you're doing. 00:20:59.361 --> 00:21:05.111 And we spent a huge amount of this inventing terminology that allowed this 00:21:05.331 --> 00:21:10.511 modular thing, that you had to build this entire protocol infrastructure so that 00:21:10.591 --> 00:21:16.491 you could plug in a DSA and remove it, and the protocol doesn't change at all. 00:21:17.071 --> 00:21:21.491 I, I mean, it's built that you plug it and pull it out, and it functions, and 00:21:21.571 --> 00:21:26.711 as you say, incredibly quickly we're ans- we're, we're addressing that question. 00:21:27.201 --> 00:21:28.651 Uh, it's part of the database. 00:21:28.991 --> 00:21:34.531 And so the, the master protocol itself is this amazing thing that has 00:21:34.591 --> 00:21:39.611 come out of Remap-Cap that, by the way, many people have used, copied, 00:21:39.811 --> 00:21:42.701 which is fantastic, modeled after. 00:21:42.771 --> 00:21:47.811 It in and of itself is an incredible sort of scientific achieve- achievement 00:21:49.500 --> 00:21:53.000 Steve Webb: Um, and, um, uh, I've spent a lot of time in the last couple of 00:21:53.080 --> 00:21:59.960 years, talking to clinicians or even clinical trialists who've got experience 00:22:00.080 --> 00:22:05.320 with conventional clinical trial designs about adaptive platform trials, and 00:22:05.360 --> 00:22:10.860 it's the concept of the domain, which is one of the most difficult concepts 00:22:10.940 --> 00:22:15.680 to try and articulate and explain in a way that, uh, people get it. 00:22:16.020 --> 00:22:20.721 But I've got a new technique which is working really well, which is that I 00:22:20.801 --> 00:22:25.600 tell them, if the goal of the platform trial is to try and design the best 00:22:25.660 --> 00:22:32.421 possible Big Mac, then what you have is the components of the Big Mac as domains. 00:22:32.760 --> 00:22:36.401 So there's a pickle domain, yes or no for pickles. 00:22:36.700 --> 00:22:38.780 There's a beef patty domain. 00:22:38.940 --> 00:22:41.400 Do- is it flame grilled or fried? 00:22:41.520 --> 00:22:46.360 Um, and, uh, people suddenly get the idea of what a domain is. 00:22:46.401 --> 00:22:48.940 But we had to go to a Big Mac to make progress. 00:22:50.362 --> 00:22:57.263 Scott: And we then had to name the Big Mac is when you get all of the pieces of the 00:22:57.342 --> 00:22:59.442 domain that work, what do we call that? 00:22:59.502 --> 00:23:00.683 And we called that a regimen. 00:23:01.282 --> 00:23:04.902 So each piece together, the Big Mac itself is another regimen. 00:23:05.263 --> 00:23:08.342 We, we have patient subgroups where there may be differential 00:23:08.502 --> 00:23:11.882 effect, and so we named this and named all these pieces to it. 00:23:12.622 --> 00:23:15.042 S- so we went through this amazing thing. 00:23:15.103 --> 00:23:16.662 We set up the statistics. 00:23:16.742 --> 00:23:18.582 We, we talked about it. 00:23:18.642 --> 00:23:23.402 We set up response adaptive randomization can be done within the trial. 00:23:23.502 --> 00:23:26.262 We set up the entire thing as Bayesian. 00:23:26.842 --> 00:23:30.862 Uh, and interestingly, a foreshadowing of, of medical papers that come 00:23:30.943 --> 00:23:33.002 out of this have zero P values. 00:23:33.582 --> 00:23:36.402 All Bayesian triggers in all of this. 00:23:36.802 --> 00:23:41.882 So this is kind of all set up, and as you d-- as you, as you've said, when 00:23:41.943 --> 00:23:46.382 we had meetings maybe two thousand seventeen, everybody would come together. 00:23:46.422 --> 00:23:52.002 We've got this new protocol, um, uh, in this Genevieve O'Neill, who's 00:23:52.062 --> 00:23:53.802 not working on Remap CAP anymore. 00:23:53.882 --> 00:23:57.002 She was on every one of these calls, I think, in, in making 00:23:57.042 --> 00:23:59.263 this go forward from Australia. 00:23:59.682 --> 00:24:03.882 But that we had more investigators than patients at the time. 00:24:04.562 --> 00:24:07.862 Uh, we're enrolling CAP, and then 00:24:08.200 --> 00:24:11.500 Steve Webb: there, there, there, there was celebrations, there were fireworks, 00:24:11.601 --> 00:24:15.401 uh, there was champagne popping when we finally had more patients 00:24:15.460 --> 00:24:17.360 enrolled than we had investigators 00:24:18.206 --> 00:24:18.386 Scott: Yeah. 00:24:19.086 --> 00:24:23.566 And by the way, we still, uh, after the pandemic's over, we're 00:24:23.626 --> 00:24:25.407 back to this question of CAP. 00:24:25.726 --> 00:24:29.007 These patients are absolutely informing conclusions, and we've 00:24:29.046 --> 00:24:30.986 got exciting conclusions within CAP. 00:24:31.046 --> 00:24:39.507 But meanwhile, um, a, a-- this Wuhan disease comes up, and it was interesting 00:24:39.606 --> 00:24:45.306 looking back at the, the genesis of this from early 2020 in January. 00:24:45.366 --> 00:24:52.767 There's this weird thing going on until March when it became part of REMAP-CAP 00:24:54.644 --> 00:24:58.724 Steve Webb: So one of my favorite emails from, uh, Remap, uh, Scott, 00:24:58.904 --> 00:25:05.304 is the one I sent to, um, Green, who is the extraordinary, amazing 00:25:05.405 --> 00:25:10.964 project manager that, um, uh, carried Remap CAP through the pandemic. 00:25:11.464 --> 00:25:18.504 Uh, Cameron sends me, um, news links to this new disease in Wuhan, and he 00:25:18.584 --> 00:25:24.944 copies, uh, it to Colin MacArthur, and, uh, Cameron says, uh, "Do you think, 00:25:25.024 --> 00:25:30.445 uh, we need to be, uh, worried about what's happening in, uh, in, in Wuhan?" 00:25:31.105 --> 00:25:36.504 Um, and, um, uh, my response to Cam is, "Oh, you know, Cam, in the last 00:25:36.544 --> 00:25:40.584 couple of years there have been these sort of little mini outbreaks. 00:25:40.624 --> 00:25:44.944 They, um, uh, cause a little bit of excitement and then they, uh, 00:25:45.124 --> 00:25:47.364 disappear, uh, reasonably quickly. 00:25:47.864 --> 00:25:51.304 That's what I expect will happen, uh, to this one. 00:25:52.364 --> 00:25:56.724 besides, um, no pandemic in 2020 please. 00:25:56.745 --> 00:25:58.605 We're close but we're not ready." 00:25:59.962 --> 00:26:00.943 Scott: Yes, yes. 00:26:01.522 --> 00:26:04.782 I, I, amazingly, we've said many times, "Oh, we would've been so 00:26:04.842 --> 00:26:09.602 much better off if it was COVID, uh, 20, uh, or one year later." 00:26:09.922 --> 00:26:14.862 Now, we were never gonna be ready for what it was, uh, and it was going to be around 00:26:14.902 --> 00:26:18.362 the clock, but, but it was, uh, it was… 00:26:18.823 --> 00:26:18.902 I- I… 00:26:19.043 --> 00:26:19.742 And then it hit. 00:26:19.803 --> 00:26:24.842 And one of my other favorite emails was, uh, right about that time, we were now 00:26:24.982 --> 00:26:26.862 starting to get ready to run this trial. 00:26:26.963 --> 00:26:28.742 We had enrolled a set of patients. 00:26:28.782 --> 00:26:30.602 We were talking about doing analyses. 00:26:31.222 --> 00:26:34.922 Um, and I think we had done several analyses up until this point. 00:26:35.282 --> 00:26:40.002 So I brought on two statisticians to help me, uh, Lindsey Berry and 00:26:40.122 --> 00:26:42.063 Elizabeth Lorenzi, Liz Lorenzi. 00:26:42.642 --> 00:26:46.862 And, um, they have this email of saying, "Yeah, we've got 00:26:46.903 --> 00:26:50.442 this little thing in Wuhan, but, you know, don't worry about it. 00:26:50.522 --> 00:26:52.522 Um, uh, it's not a big deal." 00:26:52.563 --> 00:26:55.962 And they look back at this, and now they've, they've been heroic in 00:26:56.022 --> 00:26:59.922 the, the analyses that have happened within Remap Cap as well, and this 00:26:59.962 --> 00:27:04.682 has now become, uh, uh, an amazing story of their involvement as well. 00:27:05.862 --> 00:27:07.122 Okay, there's an i- 00:27:07.132 --> 00:27:09.912 Steve Webb: don't know what-- I, I don't know how much you want to talk about the 00:27:09.972 --> 00:27:14.953 pandemic, but, um, I think it's worth just w- at least one anecdote, uh, Scott. 00:27:15.372 --> 00:27:21.032 The, the speed with which the platform was able to do things was extraordinary. 00:27:21.512 --> 00:27:25.452 We talked about being able to launch a new domain in three or four weeks. 00:27:26.612 --> 00:27:30.892 although there were times during the pandemic when even that felt too slow. 00:27:31.292 --> 00:27:31.452 But 00:27:31.902 --> 00:27:32.042 Scott: Yeah. 00:27:32.062 --> 00:27:32.642 Yeah 00:27:32.892 --> 00:27:36.692 Steve Webb: able to launch a new trial for, for, um, a condition that's never 00:27:36.752 --> 00:27:41.632 existed for, um, interventions, for new set of interventions in three or four 00:27:41.692 --> 00:27:45.093 weeks was, was, um, uh, was unprecedented. 00:27:45.132 --> 00:27:51.073 But, um, we had this result in November of 2020 00:27:51.098 --> 00:27:51.638 Scott: no, let's hang on. 00:27:51.738 --> 00:27:54.018 Let's not, l- let, let's sort of set this up a little bit. 00:27:54.058 --> 00:27:56.718 I do wanna shift completely to the pandemic now, so let, 00:27:56.818 --> 00:27:57.878 let's talk about the pandemic. 00:27:57.938 --> 00:28:02.438 Let's talk about the, the start of it, and I've got an email from you, you're the 00:28:02.599 --> 00:28:10.298 chair of the ITSC, where you met with, uh, uh, groups, uh, monitoring the pandemic. 00:28:10.998 --> 00:28:15.179 There are patients starting to trickle in at sites where Remap-Cap 00:28:15.298 --> 00:28:22.879 is a trial there, and I've got it on March 2nd, 2020, that you declare, 00:28:23.059 --> 00:28:24.998 "We are open for the pandemic," 00:28:26.609 --> 00:28:27.029 Steve Webb: We had 00:28:27.179 --> 00:28:27.899 Scott: at this time 00:28:29.068 --> 00:28:32.969 Steve Webb: we had a sleeping strata was in the first version of the 00:28:33.088 --> 00:28:39.528 modular protocol, and the question to the ITSC was should we activate, 00:28:39.628 --> 00:28:42.208 uh, this, uh, sleeping, uh, strata? 00:28:43.188 --> 00:28:48.988 there was a, um, a unanimity within the ITSC that that was 00:28:49.128 --> 00:28:50.609 exactly what we needed to do 00:28:53.830 --> 00:28:57.950 Scott: So now this trial that had been built, been, as you described, all the way 00:28:57.990 --> 00:29:03.251 back in 2009, uh, I'm, I'm sure pandemic preparedness has gone back further than 00:29:03.251 --> 00:29:07.570 that, but this whole idea of a platform trial being generated from that, getting 00:29:07.751 --> 00:29:12.570 funded by the EU, moving on to the different Australia thing, this idea, 00:29:12.751 --> 00:29:17.710 all of a sudden, March 2nd, 2020, the trial is now enrolling in the pandemic. 00:29:17.730 --> 00:29:20.591 So we've avoided this whole issue of, okay, now we have to 00:29:20.650 --> 00:29:22.830 design a trial for this question. 00:29:22.890 --> 00:29:23.570 We're already enrolling. 00:29:23.690 --> 00:29:25.650 By the way, we have patients coming into this. 00:29:26.350 --> 00:29:29.730 And so the things that were already in the trial, some of 00:29:29.791 --> 00:29:31.950 these shift over into COVID. 00:29:32.431 --> 00:29:33.910 Uh, all three of them shift over. 00:29:33.931 --> 00:29:37.970 I think antibiotics became a not very interesting question within them, but 00:29:38.070 --> 00:29:39.930 macrolides became very interesting. 00:29:40.010 --> 00:29:43.470 Steroids became s- s- very interesting. 00:29:44.091 --> 00:29:49.050 Now, this is the part that you sort of touched on, is now the 00:29:49.130 --> 00:29:54.930 ability within the modular approach to start to add questions to it. 00:29:54.990 --> 00:29:56.751 So now we're open for business. 00:29:56.810 --> 00:30:02.470 We already have therapies we're, we're, we're interested in, we're shifted. 00:30:02.910 --> 00:30:04.910 Now, what does this process look like? 00:30:06.685 --> 00:30:14.325 Steve Webb: So the ITSC establishes, um, processes to consider what interventions 00:30:15.085 --> 00:30:17.785 we evaluate in this, uh, new disease. 00:30:18.485 --> 00:30:23.945 We're learning about this news-- new disease in a very, uh, ad hoc way. 00:30:25.285 --> 00:30:30.865 um, um, uh, uh, my recollection, um, quite a bit in the p- in the, 00:30:30.985 --> 00:30:35.745 in the general media about all of these patients ending up in ICUs on 00:30:35.785 --> 00:30:41.655 ventilators, of, um, arterial and venous thromboembolic, uh, complications. 00:30:42.085 --> 00:30:47.965 There's actually relatively little published, even in terms of, um, uh, case 00:30:48.045 --> 00:30:51.034 reports and, uh, cohort, uh, studies. 00:30:51.665 --> 00:30:55.765 Um, uh, a-and so we have to start making decisions about 00:30:55.805 --> 00:30:57.225 what's going to be evaluated. 00:30:57.945 --> 00:31:01.225 Um, we have an existing corticosteroid do-domain, which 00:31:01.305 --> 00:31:03.644 includes, uh, hydrocortisone. 00:31:04.105 --> 00:31:09.195 We make some modifications to that domain, including, um, a d- a 00:31:09.365 --> 00:31:11.825 different dose of, uh, hydrocortisone. 00:31:12.485 --> 00:31:19.225 And we actually managed to recruit the first COVID patient into a COVID-specific 00:31:19.325 --> 00:31:25.765 domain for corticosteroids, I think on March the 6th, which is before the 00:31:25.985 --> 00:31:29.305 WHO officially declared a pandemic. 00:31:29.925 --> 00:31:36.905 So that I think reflects the, uh, the flexibility that the adaptive platform 00:31:37.005 --> 00:31:40.285 trial provided in this, uh, scenario. 00:31:40.325 --> 00:31:44.315 But we think about what else should be evaluated, relatively 00:31:44.365 --> 00:31:49.625 quickly, we put together domains to evaluate, um, uh, drugs which are 00:31:49.785 --> 00:31:54.865 thought to have antiviral activity against the, the SARS-CoV-2 virus. 00:31:55.485 --> 00:31:59.965 Um, there's a domain proposed, uh, that, uh, comprises, uh, 00:32:00.125 --> 00:32:01.485 different immune modulators. 00:32:02.305 --> 00:32:08.665 interleukin-6 receptor antagonists like tocilizumab, uh, anakinra, uh, interferon. 00:32:09.785 --> 00:32:13.625 there's also a question of whether or not patients should be routinely 00:32:13.745 --> 00:32:18.604 therapeutically anticoagulated, uh, with heparin, and that had, um, um, 00:32:18.905 --> 00:32:26.225 entered practice just seen as being, um, appropriate to prevent arterial and venous 00:32:26.245 --> 00:32:30.545 thromboembolism, given the high incidence that was, uh, was being observed. 00:32:31.705 --> 00:32:31.965 Sorry. 00:32:32.065 --> 00:32:32.545 Excuse me. 00:32:33.865 --> 00:32:36.865 Um, um, uh, there's 00:32:36.925 --> 00:32:37.165 also 00:32:37.210 --> 00:32:37.571 Scott: so let's 00:32:37.725 --> 00:32:37.795 Steve Webb: of 00:32:37.910 --> 00:32:39.070 Scott: let's set time to this. 00:32:39.151 --> 00:32:47.150 I believe, so March 2nd, uh, uh, REMAP-CAP says we're now enrolling patients 00:32:47.490 --> 00:32:50.070 COVID, suspected or proven COVID. 00:32:50.590 --> 00:32:54.471 March 6th, four days later, you're randomizing to something that 00:32:54.530 --> 00:32:55.890 was already there, the steroids. 00:32:56.791 --> 00:33:01.530 Added the, uh, immune modulation domain before the end of March. 00:33:02.310 --> 00:33:06.170 The convalescent plasma domain, I think, was added in April. 00:33:06.690 --> 00:33:12.250 Anticoagulation, as you described, is early May, uh, within that. 00:33:12.550 --> 00:33:15.971 So I believe this, this idea that you said every couple weeks we're adding 00:33:16.010 --> 00:33:20.131 them, and to some extent that felt slow, but we're doing this and adding 00:33:20.210 --> 00:33:25.831 those, uh, before just as May starts, we've added all these particular 00:33:25.890 --> 00:33:28.430 questions in a multifactorial thing. 00:33:28.451 --> 00:33:32.250 So some patients are being randomized to four and five 00:33:32.410 --> 00:33:35.410 questions at this point, which is 00:33:35.444 --> 00:33:36.145 Steve Webb: Y-y-yes, I think that, 00:33:36.291 --> 00:33:36.830 Scott: just, amazing 00:33:37.904 --> 00:33:41.324 Steve Webb: I think at the height of the pandemic, um, um, the, 00:33:41.545 --> 00:33:46.345 the, the largest number of, um, interventions that were assigned to 00:33:46.404 --> 00:33:48.965 a patient in Remap-Cap was seven. 00:33:50.162 --> 00:33:51.322 Scott: Mm-hmm. 00:33:51.322 --> 00:33:51.463 Mm-hmm. 00:33:51.565 --> 00:33:54.564 Steve Webb: that's m-m-that's multi-multi-factorial 00:33:55.298 --> 00:33:55.718 Scott: Yeah. 00:33:55.798 --> 00:33:56.518 Yes, yes. 00:33:57.758 --> 00:34:02.398 Okay, so now it's we're, we're, we're, we're getting set up. 00:34:02.459 --> 00:34:06.059 And meanwhile, uh, as you describe, it would've been nice 00:34:06.118 --> 00:34:07.358 had this been another year. 00:34:07.798 --> 00:34:09.798 We're getting the operational part of this. 00:34:09.938 --> 00:34:13.478 We have multiple databases that are contributing to this. 00:34:13.958 --> 00:34:18.419 We want to be doing interim analyses very frequently in this trial. 00:34:18.478 --> 00:34:24.198 So it is a great deal of work by a, a, a huge number of people to get 00:34:24.259 --> 00:34:27.638 this ready to start doing analyses. 00:34:27.699 --> 00:34:29.558 And then mid-June happens. 00:34:29.798 --> 00:34:29.938 Yep 00:34:30.504 --> 00:34:38.024 Steve Webb: many, many, many people literally working 14, 16-hour days, 00:34:38.524 --> 00:34:40.884 seven days a week across many countries. 00:34:41.505 --> 00:34:41.625 Um, 00:34:42.254 --> 00:34:42.274 Scott: ん。 00:34:42.424 --> 00:34:47.425 Steve Webb: Green, um, Colin, uh, the, the, uh, Lisa Higgins, who was 00:34:47.464 --> 00:34:52.005 putting the data together at Monash at that stage, the teams at Berry 00:34:54.194 --> 00:34:54.374 Scott: Yep. 00:34:54.794 --> 00:34:54.995 Yep. 00:34:55.554 --> 00:34:59.955 Uh, the UK enrolling patients, Tony Gordon, Lenny Deirdre, 00:35:00.180 --> 00:35:00.501 Steve Webb: Yes 00:35:00.754 --> 00:35:02.434 Scott: all of this, uh, amazing. 00:35:02.974 --> 00:35:08.134 So mid-June happens where, uh, we've done interim analyses, but 00:35:08.274 --> 00:35:09.854 nothing is triggered at this point. 00:35:09.935 --> 00:35:11.255 We've got triggers set up. 00:35:11.854 --> 00:35:16.415 Mid-June, the RECOVERY trial, which by the way, in and of itself is an 00:35:16.534 --> 00:35:19.434 amazing story of the RECOVERY trial. 00:35:20.014 --> 00:35:23.094 We're-- REMAP-CAP's largely enrolling severe. 00:35:23.194 --> 00:35:28.854 Meanwhile, we, during I think July, we open what's called a moderate 00:35:28.954 --> 00:35:31.094 state, uh, a step different. 00:35:31.214 --> 00:35:36.734 So we're adding to the patient population in a modular way as well, 00:35:36.855 --> 00:35:40.855 but we're enrolling only severe at this point, defined as being on 00:35:40.914 --> 00:35:44.354 intensive care-based organ support. 00:35:44.995 --> 00:35:48.094 Uh, and we went through a whole bunch of things at this point is what is 00:35:48.154 --> 00:35:53.754 the definition of an ICU, uh, because people are using non-ICU things, and 00:35:53.794 --> 00:35:59.254 we, we had to lose the notion of what, whether you're located in an ICU or 00:35:59.314 --> 00:36:01.534 do you have I- uh, ICU-level care. 00:36:01.895 --> 00:36:06.314 So there were things we had to redefine because of the surges and all of that. 00:36:06.355 --> 00:36:09.854 But the RECOVERY trial comes out with an announcement based 00:36:09.934 --> 00:36:15.014 largely on moderate patients that steroids are, uh, saving lives. 00:36:15.154 --> 00:36:21.154 And so REMAP-CAP is enrolling steroids largely in a severe population. 00:36:21.234 --> 00:36:24.274 So REMAP-CAP does what at this point? 00:36:25.785 --> 00:36:28.405 Steve Webb: Um, so I just want to, uh, uh, comment about, uh, 00:36:28.442 --> 00:36:28.623 Scott: Yep 00:36:28.705 --> 00:36:30.555 Steve Webb: amazing trial Recovery was. 00:36:30.605 --> 00:36:33.365 It was put together incredibly, uh, quickly. 00:36:34.145 --> 00:36:37.945 It, it was in some ways also an offshoot of the same group of people 00:36:37.965 --> 00:36:43.625 who'd been working on, um, um, uh, Prepare, uh, with, with, with Herman, 00:36:43.925 --> 00:36:48.705 uh, Herman Goosens, and as you said, was predominantly focusing on, um, 00:36:48.875 --> 00:36:53.625 uh, ward patients, whereas Remap-Cap was exclusively, at least initially, 00:36:54.945 --> 00:36:56.785 uh, uh, critically ill patients. 00:36:57.545 --> 00:37:04.295 So, as soon as the Recovery result, uh, um, uh, comes out, the, um, 00:37:04.545 --> 00:37:09.685 corticosteroid component of Remap-Cap, uh, in patients with COVID, um, uh, 00:37:09.945 --> 00:37:15.185 ceases recruitment, and we start this huge amount of work to try and 00:37:15.305 --> 00:37:18.705 get, uh, our results, um, analyzed. 00:37:18.825 --> 00:37:24.325 Um, only really-- O-one thing that all clinical trialists, um, um, intuitively, 00:37:24.605 --> 00:37:32.645 um, know deep in their bones um, there is nothing better when your trial has, um, 00:37:32.655 --> 00:37:40.065 uh, reached a certain conclusion, another trial reach the same, uh, conclusion. 00:37:40.385 --> 00:37:44.585 Your anxiety levels drop, uh, um, uh, enormously. 00:37:45.245 --> 00:37:50.925 Um, so, um, the WHO put together a process to try and do an individual 00:37:51.005 --> 00:37:55.625 patient meta-analysis across five or six trials that had been, uh, 00:37:55.745 --> 00:37:58.065 recruiting patients, uh, to steroids. 00:37:58.765 --> 00:38:02.285 And, um, that all happened, uh, at light speed. 00:38:02.755 --> 00:38:09.145 Um, the Recovery result, um, was, um, uh, released, um, uh, changed global 00:38:09.265 --> 00:38:12.225 practice instantly, um, in June. 00:38:13.105 --> 00:38:17.805 there was a, a manuscript, I think, um, I'm not sure precisely when it was 00:38:17.885 --> 00:38:25.345 through, uh, July or August, and but it was September when, um, the WHO, 00:38:25.785 --> 00:38:31.465 um, IPDMA was published together with the primary manuscript of these other 00:38:31.485 --> 00:38:34.085 steroid trials, including Remap-Cap. 00:38:34.505 --> 00:38:39.125 And, um, uh, the Remap-Cap results were strongly supportive of the result 00:38:39.185 --> 00:38:43.585 that had come from, uh, Recovery, uh, with five or six hundred patients. 00:38:43.885 --> 00:38:47.805 Uh, my recollection, we were sitting on a, uh, uh, posterior 00:38:47.885 --> 00:38:52.785 probability of ninety-three percent, uh, superiority for hydrocortisone 00:38:52.905 --> 00:38:55.025 over, uh, no hydrocortisone. 00:38:56.045 --> 00:38:59.785 we wouldn't have been too far away from, uh, triggering with some, 00:38:59.885 --> 00:39:04.085 uh, additional recruitment, but it provided strong supportive evidence of 00:39:04.145 --> 00:39:10.125 the benefit of this cheap, available treatment for this dreadful disease. 00:39:11.782 --> 00:39:15.622 Scott: Um, uh, it was another really neat thing of the Bayesian 00:39:15.742 --> 00:39:21.203 approach that at that time we stopped because care had changed. 00:39:21.242 --> 00:39:22.862 We couldn't give a control anymore. 00:39:23.402 --> 00:39:28.442 And so we got to read this out, and it was this 93% probability of superiority. 00:39:28.842 --> 00:39:34.982 It wasn't that we're non-significant, it was the, the-- in the paper, we 00:39:35.043 --> 00:39:37.242 didn't need adjectives, moderate. 00:39:37.302 --> 00:39:43.022 It was there's a 93% probability this is beneficial, uh, which was such a 00:39:43.082 --> 00:39:47.962 cool part and a simple thing and such a straightforward scientific thing 00:39:48.102 --> 00:39:52.142 about a clinical trial that was, was a positive of the Bayesian thing. 00:39:52.992 --> 00:39:53.812 Steve Webb: We, we, uh, Scott, 00:39:53.922 --> 00:39:54.223 Scott: Now, 00:39:54.292 --> 00:39:54.452 Steve Webb: two 00:39:54.582 --> 00:39:54.703 Scott: yeah 00:39:55.013 --> 00:39:57.173 Steve Webb: we, we need, we need two T-shirts. 00:39:57.273 --> 00:40:00.452 One is, "This is a p-value-free zone," and the other is, 00:40:00.474 --> 00:40:00.954 Scott: Yes 00:40:01.212 --> 00:40:03.212 Steve Webb: treatment, we estimate treatment effect." 00:40:04.950 --> 00:40:05.710 Scott: Yes. 00:40:06.030 --> 00:40:10.091 Oh, I thought you were gonna go to the T-shirt that you wore much of 2020, 00:40:10.750 --> 00:40:13.091 um, that I, I will always remember. 00:40:13.551 --> 00:40:16.131 Uh, it had a picture, it was emoticon-based. 00:40:16.190 --> 00:40:21.811 It had a picture of a magnet and then a pile of, uh, shit next to 00:40:21.870 --> 00:40:25.971 it, uh, which was, which was quite apropos for what was going on, yes. 00:40:26.910 --> 00:40:27.811 Um, okay. 00:40:28.170 --> 00:40:31.910 So at that time then, Remap Cap adds the moderate state. 00:40:32.710 --> 00:40:39.311 It, um, it's now triggering a number of conclusions, uh, and we'll get to 00:40:39.370 --> 00:40:41.310 some really important ones of those. 00:40:41.671 --> 00:40:47.131 But it's also, um, cooperating with other platform trials in a 00:40:47.290 --> 00:40:49.670 multi-platform randomized trial. 00:40:49.790 --> 00:40:55.850 So it's working with Operation Warp Speed, um, and the trials, it's working 00:40:55.930 --> 00:41:01.510 with a Canadian one where we all pool our data together to have a single 00:41:01.550 --> 00:41:05.630 conclusion and, and a result, and we create a new thing for a trial. 00:41:06.450 --> 00:41:12.110 Uh, and then we open up a new domain, simvastatin is a- open, 00:41:12.230 --> 00:41:14.850 antiplatelet domain is opened. 00:41:14.950 --> 00:41:20.390 Um, and then we start coming in with really interesting conclusions 00:41:20.470 --> 00:41:23.550 at the end of 2020 into early 2021 00:41:24.753 --> 00:41:25.092 Steve Webb: Yeah. 00:41:25.233 --> 00:41:32.492 So, uh, um, one of those triggered on Christmas Eve, Scott, and 00:41:32.666 --> 00:41:32.886 Scott: Yep 00:41:33.073 --> 00:41:37.533 Steve Webb: of us worked all the way through Christmas Day, doing 00:41:37.573 --> 00:41:39.212 the things that were necessary. 00:41:39.672 --> 00:41:41.312 I thi- I, I, I, I… 00:41:41.533 --> 00:41:44.633 That was one of the anticoagulation results, but I can't remember, 00:41:44.713 --> 00:41:48.793 uh, which one it was that, uh, triggered on, uh, December 24 00:41:48.898 --> 00:41:53.518 Scott: one was the, um, uh, likely harm of severe. 00:41:54.388 --> 00:41:54.608 Steve Webb: Yep. 00:41:55.088 --> 00:41:55.248 Yep. 00:41:55.459 --> 00:41:56.138 Scott: yep, yep 00:41:56.509 --> 00:41:59.888 Steve Webb: But before, but before that we'd had, um, again, a f- a, 00:41:59.908 --> 00:42:06.328 a, a c- a, a flurry of activity in about mid-November we'd triggered 00:42:06.548 --> 00:42:13.138 for the, um, superiority of, uh, uh, tocilizumab, an interleukin-6 receptor 00:42:13.138 --> 00:42:16.858 antagonist, compared to, uh, control. 00:42:17.448 --> 00:42:21.388 And I think the timeline is something like as follows. 00:42:22.468 --> 00:42:27.848 A week after, or it might have been, uh, 10 days after the statistical 00:42:27.928 --> 00:42:34.489 trigger, the then British Prime Minister, Boris Johnson, announces 00:42:34.489 --> 00:42:39.528 this result, uh, in a press release, uh, or in, in a press conference. 00:42:40.309 --> 00:42:44.588 Um, the following day, the treatment becomes standard care 00:42:44.628 --> 00:42:48.308 throughout the National Health Service, uh, in the United Kingdom. 00:42:49.568 --> 00:42:52.108 Uh, it's, it's, it's mid-November. 00:42:52.448 --> 00:42:54.968 Well, no, uh, uh, sorry, it's late, late November. 00:42:55.908 --> 00:42:56.508 We got that… 00:42:56.649 --> 00:42:59.248 I don't know what date we got that manuscript to the New 00:42:59.309 --> 00:43:00.648 England Journal of Medicine. 00:43:01.608 --> 00:43:04.748 Uh, it, it-- I don't know if it was in December or January, but it 00:43:04.768 --> 00:43:07.008 was published in early February. 00:43:07.048 --> 00:43:13.088 We're talking about eight or nine weeks from statistical trigger to manuscript 00:43:13.148 --> 00:43:17.928 that's been through peer review, it's had revisions done, and it's published. 00:43:18.748 --> 00:43:24.168 Uh, uh, it, it, the, it is, it is light speed in the world of clinical trials 00:43:26.811 --> 00:43:32.371 Scott: Yeah, uh, a- and likely saved tens of thousands of lives. 00:43:32.471 --> 00:43:35.351 Uh, uh, incredible therapy, uh, in it. 00:43:35.431 --> 00:43:38.131 It, it, it's amazing now the spread… 00:43:38.411 --> 00:43:43.671 Oh, so t- touching on, so tocilizumab comes out, um, within that. 00:43:43.711 --> 00:43:47.471 The anticoagulation being harmful in severe, beneficial 00:43:47.511 --> 00:43:49.691 in moderate, uh, comes out. 00:43:49.971 --> 00:43:52.971 Common therapies given, very impactful within this. 00:43:53.711 --> 00:43:57.951 The-- what's interesting, something you said, and I remember the, uh, uh, not a 00:43:58.031 --> 00:44:05.011 panic, but we triggered the tocilizumab result of superiority, and we had had 00:44:05.071 --> 00:44:10.811 a surge in the UK of patients, and so we had a good, solid result, but 00:44:10.851 --> 00:44:15.971 there were like half, uh, half the patients weren't even to 28 days yet. 00:44:16.431 --> 00:44:19.351 And so we triggered this, and the whole f- "What's gonna happen 00:44:19.371 --> 00:44:20.431 when all of these came in?" 00:44:20.471 --> 00:44:22.491 And of course, it came in almost the same. 00:44:23.091 --> 00:44:26.391 Uh, incredibly beneficial is one of this, you know, what's gonna happen. 00:44:26.451 --> 00:44:27.071 You touched on this. 00:44:27.891 --> 00:44:34.151 I think every result that REMAP-CAP came up with, with its adaptive 00:44:34.211 --> 00:44:40.811 design, its Bayesian, its RAR, its, uh, its multifactorial, was backed 00:44:40.891 --> 00:44:42.591 up by a result in a different trial. 00:44:42.731 --> 00:44:49.591 Typically after that, I think all of these results bore out w- with it, whether it 00:44:49.671 --> 00:44:56.611 was antivirals being harmful for severe patients, uh, h- hydroxychloroquine 00:44:56.671 --> 00:45:01.731 within this, the benefit of steroids within it, the benefits of the IL-6 00:45:01.791 --> 00:45:08.511 receptor antagonist, the anticoagulation result was backed up, the ACEs and ARBs. 00:45:08.591 --> 00:45:13.691 Largely all of these things, vitamin C largely doesn't seem to be a benefit. 00:45:13.711 --> 00:45:17.271 I mean, it was amazing how it kinda got it right. 00:45:18.551 --> 00:45:21.531 You know, and I don't, I don't mean to say in a doubting way, but oh my 00:45:21.571 --> 00:45:23.291 God, it kinda got everything right 00:45:24.853 --> 00:45:28.753 Steve Webb: Well, um, in, in two and a half to three years, the platform 00:45:28.813 --> 00:45:36.353 evaluated, fully tested repurposed medicines for a disease that, um, um, 00:45:36.433 --> 00:45:39.153 had never existed, uh, uh, before. 00:45:39.833 --> 00:45:41.493 There, there are a couple of results. 00:45:42.853 --> 00:45:47.313 I don't think the anticoagulation in critically ill patients was ever, um, 00:45:47.733 --> 00:45:50.093 uh, reproduced, uh, by another trial. 00:45:50.453 --> 00:45:53.553 I don't think there were other trials, or if there, if there were, they 00:45:53.653 --> 00:45:58.933 were, um, uh, um, had insufficient sample size to a-address the question. 00:45:59.953 --> 00:46:00.433 Um, one 00:46:00.510 --> 00:46:01.471 Scott: the multi-platform. 00:46:01.530 --> 00:46:06.210 It was, it was the Canadian attack trial and, and, yeah, the combining together. 00:46:06.270 --> 00:46:06.590 Right, right. 00:46:06.670 --> 00:46:06.810 Yep. 00:46:07.690 --> 00:46:08.411 Yep. 00:46:08.473 --> 00:46:11.253 Steve Webb: the, um, uh, contributions from ACTA4 and, 00:46:11.390 --> 00:46:11.511 Scott: Yep 00:46:11.513 --> 00:46:14.693 Steve Webb: a-and, and uh, uh, CAP. 00:46:14.993 --> 00:46:16.173 Attack, sorry. 00:46:16.253 --> 00:46:23.553 Um, but, um, um, um, uh, Recovery reported their antiplatelet, uh, 00:46:23.733 --> 00:46:30.333 question, um, my recollection is before we, uh, reported, uh, ours. 00:46:31.093 --> 00:46:36.293 And they stopped having recruited about 15,000, uh, patients, uh, which is a, 00:46:36.393 --> 00:46:38.963 you know, extraordinary, uh, sample size. 00:46:39.523 --> 00:46:45.833 And, um, their results were, um, um, no difference in outcome with 28-day 00:46:45.953 --> 00:46:49.273 mortality as, uh, the primary endpoint. 00:46:50.053 --> 00:46:53.433 we had this interesting result in, uh, Remap-Cap, which is a rabbit 00:46:53.473 --> 00:46:57.773 hole that we shouldn't go down, of po-possibly there being non-proportional 00:46:57.853 --> 00:47:01.893 treatment effect across the ordinal scale, uh, that we were using. 00:47:02.533 --> 00:47:08.533 But my recollection is that there was something like a 93% or 95% probability 00:47:08.633 --> 00:47:15.173 of s- of superiority for aspirin with 90-day mortality, uh, as the endpoint. 00:47:15.833 --> 00:47:19.883 if we looked at the recovery survival curves, the Kaplan-Meier 00:47:19.973 --> 00:47:25.273 curves, were really only starting to separate around, uh, uh, day 30. 00:47:25.713 --> 00:47:30.133 So it's interesting how choice of endpoints and the meaningfulness 00:47:30.193 --> 00:47:34.513 of endpoints, um, can impact on the appropriate, uh, or the 00:47:34.573 --> 00:47:38.503 generation of evidence to, um, be applied to improve patient care 00:47:40.526 --> 00:47:40.806 Scott: Yeah. 00:47:41.366 --> 00:47:47.946 Uh, another, uh, sort of amazing thing in the trial and, um, with these 17 results 00:47:47.986 --> 00:47:52.606 in COVID that you talked about is they largely, most of them had the same design. 00:47:53.407 --> 00:47:57.427 That we're going to enroll till there's a 99% probability of 00:47:57.507 --> 00:48:04.266 superiority or a 95% probability that the effect was moderate at best. 00:48:04.667 --> 00:48:08.866 Fu- we, futility, that it, it didn't achieve above a certain threshold. 00:48:09.366 --> 00:48:12.166 And well, many times we don't have a maximum sample size. 00:48:12.186 --> 00:48:14.447 We just go till one of those results are hit. 00:48:15.087 --> 00:48:19.506 And we had sample sizes of these largely with these 17 different 00:48:19.566 --> 00:48:21.267 things, different designs. 00:48:21.346 --> 00:48:25.747 We had sample sizes for the arms from about 100, and a good 00:48:25.826 --> 00:48:30.686 number of them at 100, 200, 300, all the way up to over 1,000. 00:48:31.466 --> 00:48:37.626 And the time at which it triggered and said, "Here's the answer," varied from, 00:48:37.986 --> 00:48:43.166 uh, 100 patients to 1,000 patients all spread out, and it just depending 00:48:43.226 --> 00:48:44.546 on the effect of when it happened. 00:48:44.786 --> 00:48:50.846 This incredible demonstration of the power of adaptive learning and 00:48:50.907 --> 00:48:56.286 adaple- adaptive sample size when time was so incredibly critical 00:48:56.532 --> 00:48:56.652 Steve Webb: Yep. 00:48:57.372 --> 00:48:57.532 Yep. 00:48:58.212 --> 00:49:04.352 Um, um, uh, um, the, the number of patients dying from COVID in any one 00:49:04.532 --> 00:49:09.972 week meant that, um, a week's difference in when a result became available 00:49:10.032 --> 00:49:12.612 was important, uh, to public health. 00:49:13.473 --> 00:49:19.992 Um, one of the things which, um, uh, I, I love about the Bayesian approach 00:49:20.112 --> 00:49:26.572 is, is, is just this opportunity set a statistical, uh, trigger of the 00:49:26.672 --> 00:49:30.453 amount of confidence, uh, the amount of credibility that is necessary 00:49:30.532 --> 00:49:37.493 to, um, conclude a question and then keep recruiting, frequently so that 00:49:37.612 --> 00:49:42.072 as soon as there's sufficient, uh, credibility to the result, um, the 00:49:42.172 --> 00:49:44.792 experiment, uh, uh, can be concluded. 00:49:45.692 --> 00:49:52.453 and I think if, um, I think about all of the things I learnt, uh, when I was doing, 00:49:52.572 --> 00:49:56.052 uh, biostats and epi as a master's student 00:49:56.212 --> 00:50:01.832 and thought all of these things about, um, um, uh, not answering the 00:50:01.932 --> 00:50:06.772 question until you've, uh, recruited your, uh, your proposed sample size 00:50:06.832 --> 00:50:09.972 based off a, um, a power calculation. 00:50:09.993 --> 00:50:12.492 And I thought, "Oh, these are really, really important, 00:50:12.592 --> 00:50:15.092 uh, features of, uh, design." 00:50:16.112 --> 00:50:18.352 Um, I, I, I now understand… 00:50:18.432 --> 00:50:21.232 I, I still understand why they're important, but I do 00:50:21.353 --> 00:50:22.232 think there's a better way 00:50:23.523 --> 00:50:23.663 Scott: Mm-hmm. 00:50:24.808 --> 00:50:24.928 Steve Webb: Um, 00:50:25.042 --> 00:50:25.802 Scott: Fantastic. 00:50:25.942 --> 00:50:26.422 And so 00:50:26.528 --> 00:50:36.148 Steve Webb: uh, uh, when it's appreciated so frequently the, um, uh, estimates 00:50:36.228 --> 00:50:42.668 about the size of treatment or effect necessary to run clinical trials using 00:50:42.729 --> 00:50:49.688 that approach are, um, guesses that are capable of being just wrong in a 00:50:49.809 --> 00:50:54.808 quantifiable way, wrong in the direction of the treatment effect as well. 00:50:55.808 --> 00:51:01.709 And one of the really good things that came out of REMAP-CAP was, we tested 00:51:01.768 --> 00:51:07.688 a variety of treatments because they were being used, uh, off-label where 00:51:07.729 --> 00:51:10.268 the treatment turned out to be harmful. 00:51:10.398 --> 00:51:10.668 And the way 00:51:10.668 --> 00:51:16.049 REMAP-CAP statistical triggers are set up, particularly futility, if there's 00:51:16.049 --> 00:51:21.698 an intervention that's very harmful, it triggers very quickly for harm. 00:51:22.228 --> 00:51:26.928 It's not necessary to statistically prove if that's, uh, um, a valid 00:51:26.988 --> 00:51:29.148 concept that something is harmful. 00:51:29.228 --> 00:51:31.429 You just need to know it's not effective. 00:51:32.589 --> 00:51:33.088 Some of the 00:51:33.228 --> 00:51:36.808 biggest public health impact in REMAP-CAP came from early identification 00:51:36.828 --> 00:51:40.848 of harmful interventions that were in standard care at the time. 00:51:42.042 --> 00:51:42.182 Scott: Yeah. 00:51:42.782 --> 00:51:43.063 Yeah. 00:51:43.962 --> 00:51:44.522 Incredible. 00:51:44.782 --> 00:51:46.443 So the, the story continues. 00:51:46.642 --> 00:51:48.962 The REMAP-CAP story continues. 00:51:49.403 --> 00:51:53.202 Um, w- it is still, it is still enrolling patients. 00:51:53.302 --> 00:51:56.982 I think I looked today, there are 240 sites enrolling. 00:51:57.382 --> 00:51:59.602 It's enrolling community-acquired pneumonia. 00:51:59.703 --> 00:52:00.582 It's evolving. 00:52:00.722 --> 00:52:08.182 It is ready for a pandemic, uh, onto virus or, or, or whatever happens to be next. 00:52:08.602 --> 00:52:10.982 We are ready, uh, within this. 00:52:11.042 --> 00:52:15.242 We also are getting results in community-acquired pneumonia, influenza. 00:52:15.342 --> 00:52:20.062 Uh, we're hoping to have on this show, uh, to, to talk about some of the results 00:52:20.102 --> 00:52:25.602 that are coming out, I think June 10th in, uh, Belfast, there are results coming out, 00:52:25.783 --> 00:52:29.402 so it is still doing incredible things. 00:52:30.788 --> 00:52:31.508 Steve Webb: Um, uh, 00:52:31.522 --> 00:52:32.042 Scott: s- yeah 00:52:32.428 --> 00:52:34.628 Steve Webb: it just, it, it, it just rolls on 00:52:35.834 --> 00:52:36.194 Scott: Yeah. 00:52:37.215 --> 00:52:38.674 So in-incredible. 00:52:38.735 --> 00:52:44.394 I, I appreciate you helping me start to get our hands around this beast. 00:52:44.995 --> 00:52:49.014 The, the beginning of this, the, the-- There's a lot to talk about in this, 00:52:49.094 --> 00:52:52.554 and I think we're gonna come back with lessons learned, different results, 00:52:52.714 --> 00:52:57.774 specific statistical things, response adaptive randomization results. 00:52:57.835 --> 00:53:00.334 So lots more to talk about Remap CAP. 00:53:00.354 --> 00:53:05.354 Steve, thank you very much for joining me on the origins of Remap CAP 00:53:07.092 --> 00:53:07.372 Steve Webb: Thank you, 00:53:07.706 --> 00:53:08.186 Scott: And 00:53:08.592 --> 00:53:09.732 Steve Webb: uh, great to chat 00:53:11.374 --> 00:53:15.015 Scott: And everybody else, thank you all for listening, and until next 00:53:15.055 --> 00:53:17.254 time, we'll be here in the interim