SCCM Pod-485: Better Together: The Power of Collaboration

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The power of scientific collaboration has a broad reach. During the COVID-19 pandemic, more than 7000 clinical trials were registered, with more than 100 different countries represented. Samantha Gambles Farr, MSN, NP-C, CCRN, RNFA, was joined by SCCM Lifetime Achievement Award Recipient John C. Marshall, MD, FRCSC, FACS, at the 2023 Critical Care Congress to discuss the importance of research and scientific collaboration. Dr. Marshall has been involved in research programs with researchers around the globe and is a well-known speaker with nearly 600 published manuscripts. This podcast is sponsored by Dompé Pharmaceutical.

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Transcript:

This podcast is sponsored by Dompé Pharmaceutical. REPAVID-22, a phase III clinical trial for adults hospitalized with community-acquired pneumonia and requiring oxygen support, is now enrolling. To learn more about the clinical trial, enrollment, and a site nearby, visit repavid-22.researchstudytrial.com.

Dr. Gambles Farr: Hello, and welcome to another edition of the Society of Critical Care Medicine Podcast. I’m your host, Samantha Gambles Farr. Today, I have the pleasure of speaking to John C. Marshall, MD, FRCSC, FACS, recipient of the SCCM Lifetime Achievement Award. Dr. Marshall is also the past chair of the Canadian Critical Care Trials Group and current chair of the International Forum for Acute Care Trialists. He has been involved in multiple research programs and research around the globe. He is a well-known speaker and has published nearly 600 manuscripts. In this session, we will discuss how much more is achieved through research and collaborative practice. Welcome, Dr. Marshall.

Dr. Marshall: Thanks so much, Samantha. It’s great to be here.

Dr. Gambles Farr: Thank you so much. Before we get started, I just wanted to give you an opportunity to provide any disclosures you may have at this time.

Dr. Marshall: I have a few financial disclosures. I’m chair of the Data Safety Monitoring Committee for AM-Pharma, and I’ve been a consultant to Adrenomed. I have many, many academic conflicts, including being the chair of the International Forum for Acute Care Trialists, and I received Canadian federal funding for my research.

Dr. Gambles Farr: Thank you for providing those disclosures. It’s such a pleasure to have you here with us today, and it’s a pleasure to be here with you today. We know that research plays an important part in critical care, and collaborative practice and collaborative involvement is a crucial part of that. But we are in 2023, coming out of our COVID-19 pandemic, and we’re still feeling the effects of that. Can you describe how this global pandemic has affected collaborative research?

Dr. Marshall: Sure. It’s a great question. There’s nothing like a pandemic to really sharpen the mind on what we know and what we don’t know. We saw that during the H1N1 pandemic, during the SARS pandemic before that. The challenge is, how, during a pandemic, do you actually launch trials, and how do you address the deficiencies in your knowledge? It’s striking that, during the H1N1 pandemic, if you look at clinicaltrials.gov, there were perhaps 250 trials registered. During the COVID-19 pandemic, there are well over 7000 trials registered.

I think it speaks to the fact that in January of 2020, February of 2020, we were suddenly faced with a global problem caused by a virus that we knew nothing about. We had no idea what this disease was going to be. We didn’t know whether we were going to survive it. Was it going to be as severe as MERS had been a few years previously? How should we treat patients? That really focused investigators’ minds on the need to immediately respond with research, and the global community did. Of those 7000-odd trials, more than 100 different countries were represented, including countries that you would not think of as being involved in research before, Madagascar, for example. I think Somalia had a clinical trial running.

Dr. Gambles Farr: Yes. When patients are really suffering, and we have lots of patients lost and lots of people died at the very beginning at this pandemic, people were just wondering and looking for answers, and a lot of times those answers can be found in clinical trials. In talking about research and collaboration, we talk about collaboration between institutions. But one of the things, as a nurse practitioner, we always want to make sure that we are having adequate representation, whether it’s from a point of diversity, equity, and inclusion, and interprofessional as well. Can you speak to that as it relates to collaboration?

Dr. Marshall: I would love to. Traditionally, when we have done biomedical research, we’ve done it in upper-income countries, Canada, the United States, Europe, Australia. That’s fine from the perspective of meeting the needs of people who live there, but most of the world lives elsewhere. Unless you make a conscious effort to try to expand the reach for clinical trials, and you do that by collaborating and engaging with people elsewhere, you don’t address the issues as they may occur, for example, in the global south. I think it’s a critical issue and all the more so during a pandemic.

COVID-19, when it first appeared, it was in China that the greatest burden of disease was being felt. So fundamentally important that China be involved in clinical trials. The nature of the disease sounded like, then, when it hit India or Africa, it was going to be devastating. So we really needed to think about, how do we make sure that those parts of the world are also represented in the clinical trials? The truth is, right now, our capacity to do that is quite limited. Research is still a privilege of the privileged part of this planet, but increasingly it is being democratized and being spread to other parts of the world.

Dr. Gambles Farr: Right. Even having people who do research that are trusted messengers to go into those communities and actually be able to encourage participation because we know that there’s a lot of hesitancy as it relates to research in underrepresented populations.

Dr. Marshall: Yeah, that’s a very important consideration. That was seen during the Ebola outbreaks back in 2014, 2015, where there was just a profound level of distrust with the research process. In fairness, that distrust was legitimate. We’ve certainly seen over and over again that research has been not necessarily directed to the best interests of the people who are the participants in the trials.

Dr. Gambles Farr: Yes. Thank you for that answer. In thinking about how we perform research and making sure that it’s more, for lack of a better term, user-friendly, you had previously talked about common data platforms to help researchers not have to spend time reinventing the wheel.

Dr. Marshall: Right. When one does a trial, obviously, you have to think about, what’s the question I’m asking and what data do I need to capture to answer that question? Traditionally, the way that’s been done is that each person who starts a clinical trial asks those questions to himself or herself, makes up a case report form, you fill that out for the trial, you take the data out of the medical record, which may be an electronic health record, write it down on a piece of paper, and then transfer that into an electronic database.

It’s incredibly inefficient. It’s really difficult to compare results across clinical trials. I think one of the things we definitely need to do is move to some kind of common consensus on what’s an ICU? What does it mean to be in an ICU? When does the day start? When we count how many days a patient’s been in an ICU, when did that day start? How do we write down the date? How do we describe the diseases the patients came in? What units do we use to describe the hemoglobin level? There are so many things that are trivial in many ways but absolutely fundamental to being able to share data across multiple different research venues. Having some kind of common core database is important.

There actually have been movements in that direction. An organization called ISARIC developed a database that’s used to collect data on patients with severe respiratory infection; they collected data on more than 800,000 patients with COVID-19. They’ve popularized the concept of iTools that, in building your data form, you would look at the data elements you wanted to capture and simply select them. That data element would be common across trials, and it would come with a data dictionary that described how you use that in capturing data. But I think that’s the kind of model that we need to be thinking of moving toward, so that we’re all basically speaking the same language.

Dr. Gambles Farr: And we can use it not only for data definitions, but also for tools that we use, for questionnaires that we use, to make sure that they’re validated and trusted tools as well. I think that at times in research, trying to find the right tool to use, whether it’s quantitative or qualitative research, especially for people who are not necessarily doing clinical trials, but to have that access would be very helpful to people.

Dr. Marshall: That’s absolutely true. It’s one of those things that seems trivial and that researchers tend to downplay or ignore. One of my colleagues presented a paper at this meeting looking at what the impact of the conclusions of a trial was, depending on when you measured when a patient died, and it differs. When we talk about living or dying in the ICU, it depends really carefully on when you measure, whether that patient is alive or dead, something that’s as basic as that. You draw different conclusions depending on when you measure the outcome.

Dr. Gambles Farr: That goes into whether a patient is going to be an organ donor and they’re pronounced as clinical brain death, or whether they’re going to be a DCD.

Dr. Marshall: Even beyond that. There’s a wonderful trial that was done by a French investigator a few years back; they were looking at the outcome of survival. They were measuring it at day 28 and they showed, I think, a small difference between the two groups at day 28. On day 29, there was a huge increase in mortality. The reason that occurred is that, once the patients had reached the end of the trial, the clinicians who were looking after them thought, “Okay, they’re through the trial, I can now make the decision to stop life support.” Unless we recognize that, when we measure survival, we’re the people who are determining whether the patient lives or dies, not the drug, not the intervention in the trial. You have to know what the impact is, depending on when you measure whether they live or die from the perspective of the trial, and they draw a very, very different conclusion.

Dr. Gambles Farr: That’s a very good aspect to think about. In thinking about all the things that we just talked about as far as a common data point, having different disciplines, after we’ve done all that, how do we integrate this into clinical practice, something that we see that we can use at the bedside in daily practice?

Dr. Marshall: I think there are a number of ways. The traditional way is that you run a clinical trial, you ask a single question. Does daily awakening improve outcomes? Should patients cycle when they’re in bed? Should we treat patients in the prone position when they have ARDS? You ask a single question, you say, “I think it’s going to be important if I show an x% difference in outcomes.” Typically, we use mortality as an outcome. At the end of the trial, you’ve got your results and you say, “Okay, now how do we convince clinicians to do it?” You undertake knowledge translation programs, you put it into guidelines, you set up bundles, you do all of this kind of stuff. It’s a very inefficient way of bringing knowledge to clinical practice.

This really is a big advantage of what we call platform trials because the platform trial can actually integrate the knowledge it’s generating as it’s generating it so that, by the time it reaches the conclusion, everybody is being treated that way within the context of the trial, and it makes it an awful lot easier for an ICU to implement that as standard care and to change it over time. It may well be one of the things that happens is that what worked in 1990 may not work particularly well in 2023.

Dr. Gambles Farr: And you’ve conducted a platform trial, correct?

Dr. Marshall: Correct. I’m a Canadian principal investigator of the REMAP-CAP trial. REMAP-CAP is a product of the H1N1 pandemic. We had tried to launch conventional trials in 2009. Although we were able to bring together people from many different countries and agree on what we would study, but by the time we’d written protocols, obtained funding, gotten REB approval for it, and started recruiting patients, the pandemic was just about finished. So we only recruited, worldwide, maybe 50 to 60 patients into that trial. What we realized is we needed some kind of a tool that would be running and active in advance of the next pandemic, and that’s where we came across this platform trial model.

How a platform trial differs from a conventional trial—a conventional trial, as I said, asks a question: prone positioning, particular sedation protocol. A platform trial studies a disease. It could study, for example, with REMAP-CAP, community-acquired pneumonia. You could ask, What’s the role of prone positioning in community-acquired pneumonia? What’s the role of sedation in community-acquired pneumonia? You can ask several different questions at the same time; we call these domains. A platform trial is studying the disease rather than the intervention. You can have multiple different interventions being evaluated all at the same time. Once you’ve reached a conclusion for those, you can add new ones. In theory, the trial can run forever.

Now, in REMAP-CAP, we add another little twist to this in that we use what’s called a bayesian design. Rather than saying we’re going to see a 4% difference in mortality, we say we’re going to run the trial until we are convinced that this is either better, no different, or worse than conventional care. We do it based on a hazard ratio. So the trial is running, it’s continuously looking at the data, and once it crosses one of those lines, it says you’ve reached a data conclusion, and therefore you report that result in the trial.

Dr. Gambles Farr: That can be really revolutionary in the sense of when we’re looking at H1N1 and we see this kind of global trend of these diseases becoming more transcontinental and moving over, and that helping us and assisting us and having some answers for the next one that we know is going to come at some point.

Dr. Marshall: That was the idea behind REMAP-CAP. We selected community-acquired pneumonia because that’s what a pandemic looks like. It’s typically a respiratory infection. We didn’t know COVID-19 was going to happen. In fact, it’s interesting, when the pandemic did occur and we had a meeting with our steering committee, one of the people on the committee said, “We’re not ready. We need another year.” We don’t have another year. We have to build this and add maybe 100 patients in the trial with community-acquired pneumonia.

Nonetheless, we were able to recruit well over 10,000 patients over the period of the pandemic. We did and came up with definitive answers about corticosteroids, about IL-6 receptor antagonists, about heparin, about aspirin. And we’ve still got a few more domains that are about to report and we’re going to continue the trial as long as COVID-19 is in the community. We will also continue studying community-acquired pneumonia, because COVID-19 is not going to be the last pandemic we see. We just don’t know what the next one’s going to be.

Dr. Gambles Farr: No, it’s not, and I think that that will lend to us, like I said, being able to maybe have better decision-making capability for the next pandemic that we know that’s going to come. In talking about being able to replicate and make sure that things are the way that we move in research, you used an example to DNA that I thought was very revolutionary in comparing research and DNA together. Can you explain to our listeners more about how you put those two together?

Dr. Marshall: Sure, let me try to do that. As you know, DNA is really the basic material of life. Everything that’s alive on this planet today, its existence is dependent on DNA because the DNA provides the map that determines what proteins are produced, and those proteins are what provide function. So, anything from a bacterium up to a human being to an eagle or an elephant, we all are here because we share DNA. Now, there is a fascinating book by a French biochemist by the name of Jacques Monod. He was one of the pioneers of molecular biology, one of the pioneers in understanding how DNA works. The book is called Chance and Necessity. Basically, what he argues is that life hinges on two balanced priorities, and they both are inherent in DNA.

One is necessity. DNA, the pattern of DNA, DNA reproduces itself. Because it reproduces itself, the next generations have the same DNA. They share features with their parents; that’s true whether it’s a bacterium or whether it’s a human being. That is constant over time. But there’s another really interesting element of DNA and that is that it is subject to random variation. It doesn’t happen with many of the base pairs, but over time, these can accumulate. If that random mutation helps the organism to live more effectively and to reproduce, it will be maintained in the DNA. That’s basically how, over a period of almost 4 billion years, the whole of life on the planet has evolved from a single primordial cell and the DNA of a single primordial cell.

There’s this kind of tension between the constancy of DNA and the randomness of the changes that occur. View it one way, and that’s how evolution is. Turn it around, and you’re looking at what we do at clinical trials because, in clinical trials, we want things to be constant. We want to know that if we’re comparing something between two groups, the groups are similar in every respect. Now, we could say, “Look, we’re going to recruit an equal number of men and an equal number of people with blue eyes and an equal number of people with diabetes,” but there may be thousands of ways that they differ that we’re not controlling for.

The best way of making sure they’re more likely to be similar is to randomize. The constancy of clinical research is the randomization. But the research itself is dependent on randomizing to something that you’re directing, something that is necessary. You’re getting this or you’re getting this, and when you have that constancy of the randomization scheme against this background, groups are similar because of random chance. You can then say, “Okay, the thing that made the difference between these groups is the thing that they were randomized to.” It’s interesting how research is almost reverse-engineering the history of our evolution.

Dr. Gambles Farr: Yes, our DNA. Yes, that’s amazing. When I heard you make that comparison in your talk, I was like, that is the most amazing comparison or I don’t even know what the word is at this point, to help describe what we do in research every day and how that is applicable to just how we are ourselves and DNA kind of mutates and things like that.

Dr. Marshall: That’s a very interesting thought because one could take this one step further. What we do every day we think is good. Often it isn’t. Often it’s actually harmful, as we study it. So in a sense, research is also reverse-engineering our practice. You can think of a couple of really good examples of that: transfusion. When I was a student and a resident, it was mandatory to transfuse patients when their hemoglobin dropped below 10. We then did a trial and actually the interesting thing is that the trial originally started out seeing if we could do better if we transfuse patients to a hemoglobin of 12, but we realized that there are harms associated with transfusion. So we said, “Let’s try transfusing at 7,” and this was called the TRICC trial. And lo and behold, patients did better if you didn’t give them blood. We assumed that they would be similar, but they actually did better.

Glucose control. A tremendous amount of work was put into achieving normal glycemia in the ICU. Then, the NICE-SUGAR trial showed people didn’t do as well when you did that. I think that, in a sense, research also reverse-engineers the things that we have become far too comfortable by incorporating into our practice. We say, “Look, this is the right thing to do because this guideline says that that’s what you must do.”

Dr. Gambles Farr: Right. That’s where making it very individualized to your patient and their needs also is an important aspect of interpreting research because, from one of my sayings, my grandmother said, “Everything is not for everybody.” You have to make it very individualized because at the end of the day, we are taking care of individuals. The final question is, and this one is a good one, how do we make a friendly environment for those people who are interested in research?

Dr. Marshall: I think the assumption of that question is that the environment is unfriendly. If that’s true, that’s probably one of our biggest failings right now. I don’t understand how you cannot be absolutely enthralled by research because research is asking questions. It’s the excitement of learning how things work, of seeing things that have never really been seen before. If you as a clinician see that as being hostile or fearsome or something you don’t want to do, then we have really failed in professional education in healthcare.

I think what we really need to do is, we spend so much time worrying, do I have the right answer? Am I doing the right thing? We need to do that, there’s no question. You don’t want to do something really stupid. You don’t want to, for example, as I once experienced with an error in a hospital, give enteral feeds through a central line, that’s a mistake, and I don’t disagree with that. But we all acquire a basic understanding of what needs to be done, and what’s far more important is being able to ask the right questions, not to simply recite the answers that somebody else has told you you should recite.

Dr. Gambles Farr: I think that’s a very fair point. I think also perhaps the unfriendly environment is something that we create within ourselves because we feel uncomfortable with not knowing all the answers or knowing all the most up-to-date trials, not knowing the most up-to-date research. There’s a level, I feel like, of perhaps people having impostor syndrome, of feeling like they don’t belong in that space but understanding that we all belong in that space because we’re all interested in improving the health of our patients and our consumers.

Dr. Marshall: I think that’s absolutely right. I think for trainees, it starts when you get into medical school or nursing school. Your initial reaction is, “Did I make a mistake? There’s a bunch of really smart people here and I’ve got to learn all of this because I don’t want to harm patients, and if I don’t know this, I’m going to cause harm.” But also, I think healthcare systems tend to focus on errors, quality improvement, which inherent in that is blaming people for not doing things as well as you might. I think that that’s a huge mistake.

I like to use the concept that, we talk about healthcare as often being trial and error. What funders, what policymakers, what the people who set the rules tend to focus on is the errors. They will tell you, “If you’ve got this rate of nosocomial pneumonia, this is an error and we’re going to deduct funding from you.” What they don’t recognize is the consequence of that is you change the way you describe pneumonia, so your pneumonia rates drop. That doesn’t help the patient, it simply makes your numbers look good. I think we need to move from a focus on error to a focus on trials and recognize that we can learn over time. But that requires collaboration, it requires trust in the process, trust in science, and trust in the people who are performing that science. It’s there with patients. Patients get this. Clinicians, I think, and health authorities often don’t.

Dr. Gambles Farr: I think that everything that you said is on the precipice of everything that every clinician wants to put forth in their practice. At times, they just need mentorship, guidance at times, and sometimes it just takes a little bit of a push to get people going in the right direction.

Dr. Marshall: That’s so true. I can’t tell you how many times people have said, “Well, I must do this because the guidelines say I’ve got to do it.” No, you don’t have to do that. It’s a guideline. This is something you can fall back on, but what you really want to do is what’s going to be best for that patient.

Dr. Gambles Farr: Exactly.

Dr. Marshall: So if you think this is going to be better and that’s all you have, we work with the tools we have, do it. But we have one other tool that we could be including: Randomize that patient into a trial. Then you can be certain that that patient is going to benefit or future patients are going to benefit from what you’ve done.

Dr. Gambles Farr: Dr. Marshall, thank you so much for giving us a wealth of information from a lifetime of research, learning, and applying the knowledge that you have gained in working in a collaborative manner with so many providers. We really appreciate you being on the podcast today. Is there anything you would like to say in closing?

Dr. Marshall: I would, Samantha. I’d like to thank you for asking some really good questions. This has been a lot of fun.

Dr. Gambles Farr: Thank you so much. It has been my esteemed honor to be here with you, Dr. John Marshall, SCCM Lifetime Achievement Award recipient and researcher, and just all-around inspiration to all of us. Thank you for being here today.

Dr. Marshall: Thank you so much.

This podcast is sponsored by Dompé Pharmaceutical. REPAVID-22, a phase III clinical trial for adults hospitalized with community-acquired pneumonia and requiring oxygen support, is now enrolling. To learn more about the clinical trial, enrollment, and a site nearby, visit repavid-22.researchstudytrial.com.

Samantha Gambles-Farr, MSN, NP-C, CCRN, RNFA, is a nurse practitioner intensivist at University of California, San Diego Health System in the Department of Trauma, Surgical Critical Care, Burns, and Acute Care Surgery. She also serves as adjunct faculty at University of San Diego, Hahn School of Nursing and Health Science in its nurse practitioner program.

This podcast was recorded during the Society of Critical Care Medicine’s 2023 Critical Care Congress. Access essential education online through Congress Digital. More than 120 sessions are available on an easy-to-use platform. Continuing education credit is also available. Some SCCM members receive complimentary access to Congress Digital. To learn more, visit sccm.org/congressdigital.

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