FEMALE SPEAKER: Welcome to Mayo Clinic COVID-19 Expert Insights and Strategies. The following activity is supported in part by an independent medical education grant from Pfizer Inc and is in accordance with ACCME guidelines.

LEE SKRUPSKY: All right. So obviously it's really hard up understate the impact that COVID-19 disease has had on our personal and professional lives. In the United States alone as of yesterday, there are over 2.5 million cases of COVID-19 disease and over 126,000 deaths attributable to this disease. And worldwide, over 10.3 million and similarly over 500,000 deaths have now occurred.

And just as, of course, some of the restrictions and safety precautions are being eased, unfortunately, we know that numbers are increasing in many parts of our country and throughout the world. So this is, of course, an issue we know we're going to be facing for sometime going forward.

Not surprisingly amidst this public health crisis, numerous existing medications have been explored and used in the treatment and prevention of COVID-19. And also investigational therapies are being pursued and developed at rates not seen before. And so as key members of health care teams everywhere, pharmacists continue to play a vital role in the frontline efforts against COVID-19.

So today we're really excited to have with us six panel members, each from having a diverse role in those frontline efforts against COVID-19. And they're here to share with us their experience and also any questions that you all have related to such issues. I'll note that we are socially distanced here and have a number of measures in place to keep us all safe.

So I'd like to introduce for this session, as far as moderators, will be both myself and Dr. Cristina Rivera Dr. Rivera is an infectious disease pharmacist at Mayo Clinic Rochester. I serve as a pharmacy education manager and critical care pharmacist also at Mayo Clinic Rochester.

We have, as I mentioned, six panel members with us today, each pictured here on this slide. And I'd like to briefly introduce each of them so you can understand what their backgrounds are and start thinking about questions you might want to pose to any member of this group.

So I'll start with Dr. Chris Arendt. Chris is a senior clinical manager who oversees the heart and lung transplant and the Cardiovascular Surgery Pharmacy Practice at Mayo Clinic Rochester. Since 2001, Dr. Arendt has been responsible for disaster preparedness planning and resources for the Department of Pharmacy. He sits on the executive Health Care Incident Command Committee, is the pharmacy content expert, and has been actively engaged in numerous disaster response scenarios through the HIC structure. And, of course, most recently this has included the response to the ongoing COVID-19 pandemic.

Dr. Anna Bartoo is the senior manager of research pharmacy at Mayo Clinic in Rochester, Minnesota. Anna's team of research pharmacists and technicians have been involved in setting up numerous inpatient and outpatient clinical trials and emergency use protocols for the treatment of COVID-19. The clinical trials setup process has been greatly accelerated for COVID-19 trials with trial activation accomplished in days when it usually takes months.

Dr. Laura Dinnes is the pediatric antimicrobial stewardship and infectious disease pharmacist here at Mayo Clinic Rochester and has been in this role for a little over a year. Throughout COVID-19 she has been involved with applying the pediatric literature to help create and update pediatric COVID-19 Ask Mayo Expert content, evaluate order sets, and standardize the approach for obtaining remdesivir for compassionate use.

Dr. Kirstin Kooda currently practices primarily in the medical and surgical trauma ICUs and also a little bit in the emergency medicine setting. Kirstin is the pharmacist representative of the Critical Care Education Committee and has provided a pharmacy viewpoint on the ICU-focused COVID-19 educational efforts. She's also participated in remote rounding within the eICU for a COVID-19 unit located in New York.

Dr. Bradley Peters is also a critical care pharmacist, specializing in the medical and surgical ICU settings. Brad has had the experience of staffing at the very onset of COVID-19 experience and has since spent multiple weeks on the COVID-19 designated unit assisting with pharmacotherapy decisions for these patients.

Last but not least, Dr. Ryan Stevens is an infectious disease and anti-microbial stewardship pharmacist. He started at Mayo Clinic in 2019, prior to which he was an ID specialist at Providence Alaska Medical Center for eight years. He's been involved in the COVID-19 efforts through involvement in antimicrobial stewardship program and COVID-19 flag rule design, COVID Literature Review Task Force within the ID division, and lastly COVID-19 therapeutics Ask Mayo Expert module review team. So welcome and thank you for joining us, everybody.

So the objectives for the session today. We're going to describe how pharmacists can be involved in a health care incident command response to a pandemic. We're going to identify medications that are currently being used or investigated in the treatment of COVID-19 disease or both in some cases. And then lastly, discuss pharmacotherapy treatment considerations for critically ill patients with COVID-19 disease.

So, again, we want this to be a very interactive session. We've set up a Slido event for anybody to submit their questions to us anywhere. All you need to do is go to www.sli.do and the event code is 70012.

You can see that in the screenshot in the lower left here. Enter that code, join the event, and then you'll see a bar where you can type any question you'd like to ask to any of our panel members. And you can also note the little like symbol. You can like certain questions, and that will elevate them within the list of questions if that's something you'd like to see answered as well.

So we're going to start first. We have a question that we'll begin with, one for each of our panel members in their respective areas of expertise to give everyone a little bit of time to start thinking about questions and enter those into Slido. And Christina and myself will then start troubleshooting-- or not troubleshooting, rather, but directing those questions to our panel members.

So we'll start with Chris Arendt. So Chris, obviously, I think you have a unique role that maybe even some of us in pharmacy may be less familiar with of the pharmacist's role that you play in this effort. And so the first question I'd like to ask is is to help us understand that a little bit more, and could you just explain for us what has been the primary role of the pharmacists on the HICS team during the COVID-19 pandemic?

CHRIS ARENDT: Thank you very much. I'd like to speak, perhaps, out of turn on behalf of all the panelists to first off say thank you very much for this opportunity, and thank you to the education committee and the group for letting us have this opportunity to share our unique perspective on COVID-19 and the role of the pharmacist.

So what does the pharmacist do within HICS, especially as it relates with COVID-19? And I think that the simple answer is we are a bridge. We are a bridge across many different specialties.

We have specific roles. We have an actual job action sheet within HICS, the Hospital Incident Command, that includes things such as being the pharmacy unit leader. You literally are the person who is the liaison for pharmacy. It's much like having a director role where you essentially get all the questions funneled to you about anything medication related or pharmacy distribution related, inpatient or outpatient. And then you have to use your resources to be a liaison within the department to get questions answered and then filtered back up through HICS.

HICS is part of the national incident command system, and that incident command system is a top down command system. They have one leader. That one leader sets the vision, sets the pace, sets the cadence for what's going on in a disaster, and then uses essentially each of several direct leadership roles, whether it's a medical operations chief, whether it's a planning chief, whether it is a finance chief, to essentially be the person to get things done.

HICS is the action arm of Mayo. So direction comes in that, hey, there's a pandemic. We need stuff.

And so that stuff goes through each of those different command groups and eventually funnels down to each of the groups that supply those sorts of things or stuff, whether it's masks and gowns, whether it's investigational things like remdesivir, or maybe even, how are we going to try and coordinate this within the structure of our system, of our existing Mayo system?

So you could be the pharmacy unit leader. You could also have a role that's unique. Pharmacy is just one of several groups of the ancillary services that Mayo has. That includes things like lab, radiology, morgue, ECG, and respiratory therapy. Pharmacy is just one of the components within that group.

So Mayo has a ancillary services director, and that's the role that I've been fortunate enough to have within this particular disaster. And I'm supposed to essentially, as a pharmacist, work with each of the different groups, each of the different specialties, to ensure that their needs are met and followed up through the medical operations chief. That means that the pharmacy unit leader got to report to me, and I got to help try and facilitate what that is, what's going on, and be an interpreter for what those needs are.

It requires, like I said, to be a bridge, to be a liaison. Pharmacy bridges the medical information that's out there, as well as the getting of things, whether it's the actual securing or sequestering the products necessary. Whether it's a content expert for things like, hey, we're out of hand sanitizer. We can't get it.

We need people who have possibly a chemistry or an understanding of the physical properties of chemicals to be able to help us. Oh, and we need a distributive method to do this. And oh, hey. We have to somehow go beyond use dating on this stuff. And do we have any of the manufacturing capabilities and capacities?

And meanwhile, you also have other groups that have similar type expertise. Lab is an exceptional group of people. Lab is amazing at Mayo Clinic, among the other specialties.

And they have a deep, obvious understanding of chemistry, but they didn't have the resources or the, if you will, expertise within the distributive piece and then some of the beyond use dating and things that you need when you actually have to give a product to people. So we got to liaise with them to use their expertise and to essentially use our expertise in combination. So pharmacy has many roles, but mostly as a bridge.

LEE SKRUPSKY: Thank you, Chris. That's really helpful, I think, for us to start understanding the breadth of what goes on through that work. So I encourage everybody to give some thought, as you heard Chris explain this very unique role. I imagine it might spark some questions as we go along here to learn a little bit more detail about that experience. Christina?

CHRISTINA RIVERA: OK. My next question is for Dr. Bartoo. We've seen different drugs come out in different types of research settings for treating COVID-19. So I'm wondering if you can explain to us what is the difference between a drug in a traditional study versus a drug being used under EUA, Emergency Use Authorization, versus an IND, Investigational Drug Usage.

LEE SKRUPSKY: Excellent. [INAUDIBLE].

ANNA BARTOO: Sure. So to begin with when a drug is being used for a clinical trial, typically it's being used under what is called an IND, Investigational New Drug Number. And along with that IND, there's a process involved in which the FDA reviews the animal data, preclinical trial data, and gets authorization to use that drug.

Along with using a drug under an IND, there are a number of requirements. Typically informed consent and then also a number of record-keeping requirements. And that's really the code of federal regulations is very specific about what's required to use a drug under an IND. And you have to keep records all the way from receipt, distribution, destruction, the whole lifecycle of the drug down to the patient's specific level.

So using a drug under an EUA, Emergency Use Authorization, can only be used when-- in an emergency has been declared by either the Secretary of Homeland Security, Secretary of Defense, or the Secretary of the Health and Human Services. So once an emergency has been declared, then the FDA commissioner has the authority to authorize a drug and other things under emergency use authorization.

And these are typically emergencies that involve chemical, biological, radiological or nuclear agents. So the EUA allows for the development of medical countermeasures, which includes drugs, biological products, and devices. So the remdesivir clinical trials were really done in a rapid manner.

At Mayo, we opened the first one within six days of being notified of the trial, and we participated from the end of March through pretty much the end of May. And that is when the information was presented to the FDA to allow the approval for the emergency use authorization.

So some differences under EUA is informed consent is not required, but they do require patients to be notified and explained that it's an investigational medication. They have to be explained some of the known risks. They have to also know some of the alternatives available, and they have to understand that they have the right to refuse. They don't have to accept a drug under emergency use authorization.

And then the record keeping is not as rigorous as it is under an IND. It's mostly-- the burden is on the manufacturer. So the manufacturer has to keep track of the number of doses and who they shipped it to, but it doesn't have to be done at the individual patient level.

Another thing that's interesting that can be done under an EUA is that a drug expiration can be extended. So if you have a drug that's expired, they can use the EUA process to allow that drug supply to be used in an emergency situation, which is interesting and intriguing to pharmacists to think about.

CHRISTINA RIVERA: A follow up question about supply. Do you have any updates on remdesivir supply [INAUDIBLE]?

ANNA BARTOO: Sure. So originally Gilead donated their entire supply, and that has been being distributed through the Minnesota Department of Health. We've gotten about four or five shipments, and the last shipment is actually arriving today.

Minnesota Department of Health has kept very close contact with all of the medical facilities across the state to know both the number of hospitalized patients that they have, the supply of remdesivir on hand, and then what their use pattern is if they're seeing admissions and use increase, decrease, plateau. And they've done a very good job of moving supply around the state to those who have the most need.

After the shipment this week, it was a little bit unknown as to what the supply of remdesivir was going to be. But it was just announced yesterday that Gilead has, I think about another 900,000 vials that will be introduced into the supply chain. The interesting thing about this is now they've been given permission to charge for the vials, so each vial of remdesivir will be about $500.

And I think the course-- total course of therapy, depending on if patients get 5 or 10 days, should be between about $3,000 to $5,000. It was noted in the explanation of Gilead of setting the price is that by reducing a hospitalization day, you decrease expenses by about $12,000. So they felt that the cost of the drug justified the reduction in the hospitalization.

I see some disagreement here. Do you want to make a comment?

KIRSTIN KOODA: It's probably not gonna be a correct comment.

[LAUGHING]

Sure, I guess. I mean-- this is Kirstin. I have a problem with the pricing personally, because I think that the data isn't that strong that all patients who get it have a decreased hospital stay. It seems like it's the early administration. And potentially if you're giving it to somebody as they develop symptoms, that's the benefit.

But a lot of our usage is when they're in the ICU. They're prone. They're ventilated. And at that point, it feels like it's probably a little bit too late to be that effective. So I just have a personal affront that the company is saying that it works that well so we'll charge this much.

ANNA BARTOO: Yeah. Yeah. That's an excellent point. And it's interesting because they also made a comment about pricing it so that it could be affordable by developing countries. And outside of the United States, I think we'll see some generic manufacturers, which is also an interesting discussion point.

CHRISTINA RIVERA: All right. Great. Thank you. Our next question is for Dr. Dinnes. So it's my understanding we have now had a couple pediatric patients in Mayo Rochester with COVID-19. Can you describe for us how the presentation in children of this disease is different than in adults?

LAURA DINNES: Yes. Thank you for the question, Christina. So I think we know now that many children are still asymptomatic with new studies coming-- or papers coming out in the last week even. Up to 50% of kids can still be asymptomatic. And I think even when we do have children presenting, we are lucky that they are presenting with mild to moderate symptoms.

They do present with similar symptoms to adults, just usually in a milder case. The two most common symptoms are still fever and shortness of breath in pediatric patients and GI symptoms have been increasing.

One of our peds pharmacist jokes about the fact that we've had an increase, it seems like, in appendicitis cases. And maybe that is some sort of abdominal component to this since we're seeing all these kind of atypical presentations in a lot of our pediatric patients. They're really telling pediatric providers and anyone caring for pediatric patients to be vigilant with any new change in a pediatric patient.

One thing that I think is different, and I don't know if it's that it's not happening or that they can't necessarily explain it, is we've heard about this loss of taste or smell. We haven't seemed to hear about any cases of that in pediatric patients, but that may just be they don't necessarily with the younger kids know how to explain that. So that's one difference.

Yeah. I think that's pretty much it.

CHRISTINA RIVERA: I know I've read, too, about Kawasaki disease. Can you explain what that is and what would we look for in a pediatric patient with that?

LAURA DINNES: Yeah. So yes. Kawasaki disease is getting a lot of press these days, and it is one of the leading causes of cardiovascular disease in pediatric patients, with up to 25% of patients that get Kawasaki disease going on to have coronary artery aneurysms.

And so essentially Kawasaki disease, we use that mnemonic CRASH and burn to think about the symptoms that it causes. And there is no diagnostic test for it. So really it's a diagnosis based off of exclusion and clinical symptoms.

So CRASH standing for Conjunctivitis, Rash, Lymph Adenopathy, Strawberry Tongue, which is like a swollen tongue, or it could even be swollen lips or dry lips, and then H stands for hands and feet. So they typically have swollen hands, which, if they present later, they then also have peeling potentially of their hands and feet. And then the burn is the fever. So to have a diagnosis of Kawasaki disease, you have to have a fever for greater than five days and then four of these other clinical symptoms that are included in the CRASH.

And so what this MIS-C or PIMSTS, all these different acronyms for it, essentially is-- and there's just two papers that just came out actually yesterday in The New England Journal of Medicine, one from the CDC and one from cases in New York, that showed that about 70% of patients are presenting with either-- with actually four different systems, problems in different systems. So GI, cardiovascular, respiratory, and then either hematologic or mucocutaneous systems are being affected.

And what's interesting about this inflammatory condition that we are thinking is associated with COVID is that it's been normally affecting older children. So Kawasaki usually affects children less than five years old, or that's where it's more commonly infected. There are few reports in adults. But the average age for this condition is closer to nine or 10.

And also the older children are presenting with more of a shock picture as well. So they're presenting with hypertension, hypotension, tachycardia, tachypnea and the younger population is still presenting with these normal Kawasaki signs.

And so how we normally treat that is-- or Kawasaki disease is kind of how we're approaching this MIS-C right now. And so we're using IBIG essentially, pretty much as the mainstay. Some will receive corticosteroids. And then a lot of them will get aspirin after, and that's mainly for an antiplatelet effect so that they can have a follow-up with cardiovascular teams to make sure that they aren't at any risk for any cardiovascular dysfunction.

CHRISTINA RIVERA: [INAUDIBLE] mentioning anticoagulation. That's a great time to transition over to Lee for our critical care questions.

LEE SKRUPSKY: Yeah. Thanks, Cristina. So yeah. We're starting to get a couple questions coming in too, and so I was going to ask a couple general questions initially to both Kirstin and Brad. I think I might do one general question in the field of critical care for you both to comment on, and then maybe dive into one of the questions getting into therapeutic discussion as well.

So start first with-- and it's come up already some comments on assessments of the evidence for the different therapies that are being used and being explored. And so certainly I think especially in the early going there were many therapies that were being considered and or used for critically ill patients based on pretty limited evidence, and perhaps based more on either anecdotal experience, or using extrapolation from previously encountered populations.

At this point in time have we observed some swing back toward a more consistent evidence-based medicine approach where we're considering the strength of that evidence as we make these decisions. And whereby investigational therapies might be less commonly applied in practice outside of the context of a clinical trial.

KIRSTIN KOODA: Yeah. So this is Kirstin again. That's a great question. And we are very fortunate here in that our physicians across the board believe very strongly in evidence-based medicine.

So while it's true that all over-- certainly like Med Twitter and social media and what we're observing in other sites that were epicenters, people we're using a lot of very experimental therapies without a lot of evidence. We here did not jump into doing that. They developed, with a lot of Ryan's help too, a COVID watch dog group to figure out who we should be using these investigational therapies in, even before there were full on trials. And from a critical care standpoint, our providers had been very aggressive about sticking to good, solid basic critical care.

Since we have spent a lot of time, especially in the sepsis literature. If you look, trying to find that immunologic bullet to fix sepsis over decades, and we never have found anything. So there I think the general instinct of the critical care providers here is that a lot of this [INAUDIBLE] therapy for the vast majority of patients probably isn't going to do anything, and so they haven't jumped to using it.

LEE SKRUPSKY: Brad, did you want to add anything to that?

BRADLEY PETERS: So this is Brad. Yeah. I would probably echo what Kirstin said. I think being in the Midwest we had the benefit of maybe being a little bit on the outside and having the ability to watch what other people were doing.

Because yeah, people jumped on therapy very, very quickly. And like you said, Twitter and Facebook and all the other things kept coming out saying, oh, you should do this. This is magic. This is magic. Let's keep doing this.

By the time I think we got a lot of our COVID stuff, a lot of it had been dispelled. And so I would say that we've done a pretty good job of being on top of more evidence-based medicine decisions.

LEE SKRUPSKY: So that's actually-- I'm going to change the question I was gonna ask second then, based on what you just said, because it lines up perfectly. So one of the questions that was submitted here is how much has Mayo Clinic been interacting with, for example, New York, Washington, elsewhere in regards to treatment approaches in the ICU while the pandemic is still early on?

I mean, I know I can comment, being on some of those LISTSERVs. Certainly there's a lot of mechanisms in today's world where I think a lot of things are being able to rapidly share or disseminate experiences. But I open up to you guys to comment further on any additional contacts or communication from the panel's experience.

BRADLEY PETERS: So I would say that most of my experience has been through the LISTSERV. I have not specifically reached out a lot to specific pharmacists on those frontlines and whatnot. Have you guys done that? OK. I'll let Kirstin talk about that, because I typically follow the LISTSERVS.

LEE SKRUPSKY: Well, I know Kirsten I think, mentioned in the bio, too, had a unique experience through the eICU in connecting with the New York unit. So please, Kirsten.

KIRSTIN KOODA: Yeah. So one of the first things that Mayo did is Dr. [INAUDIBLE] and Dr. [INAUDIBLE], both on the research side with SECM's Discovery Network, set up a huge international network of database so that people could enter their patient experiences. And we could have a centralized, accessible database to understand the big picture of this disease state. And I think there are over 3,000 patients they have now from all over the world. So that was one of the biggest things that Mayo did, or that representatives of Mayo put together publicly.

From a working with New York standpoint, when the New York governor announced that they were going to restrict intrastate license procedures so that if you were licensed to practice in any state, you could also practice in New York without going through a lot of paperwork, that was when Dr. [INAUDIBLE] and eICU really reached out to smaller hospitals and said, look. We want to do this. We want help. What can we do for you?

And I happened to be in the right place at the right time. So it was a week that I was on some research time and I got called over to the eICU. And I basically helped them remotely around from a pharmacy standpoint.

So these were hospitals that were very small, totally overwhelmed. There were pediatric cardiologists rounding in the adult ICU, nurse practitioners that weren't ICU experienced. And so what we provided for them was really the good solid metric method of patient rounding that Dr. [INAUDIBLE] has really championed throughout Mayo's international ICU teaching experience. So it wasn't so much the our specific ICU expertise is more as it was a comfort with the patients [INAUDIBLE] critically ill nature and kind of a very systematic approach to going through things that we really provided.

LEE SKRUPSKY: OK. Thank you, Kirstin. So let's kick it over to Christina. I know you've got a question for Ryan. I want to get him involved here, too.

And then I'm going to come back probably after that just to give you guys a heads up. Question that has something to do with starting with dexe and ending in methasone that I figured you might anticipate.

CHRISTINA RIVERA: Yeah. Kirstin mentioned your involvement in the treatment guidelines at Mayo and the COVID team and the COVID service for infectious disease. So can you just describe your role as a pharmacist that you played with this?

RYAN STEVENS: Yeah. Thanks, Christina. I think the first thing that's worth mentioning is that there's been, obviously, a team of the ID pharmacists, including yourself, and Laura and Lynn Estes that have done a fantastic job, I think, sharing the burden of a lot of different aspects and different roles that have had to be taken on in the face of the pandemic. So props to you all for all your involvement as well.

And so my piece where I fell in the cascade of things was to do and be involved with the development of the local Mayo guideline. And so initially this was sort of a roughed in guideline that was available from the infectious diseases division website that was put together by a small group of leaders from the ID division that I also was able to sit on that from a pharmacist perspective. And this was really early on when Anna was enrolling early on in the remdesivir trials.

And we weren't seeing a ton of patients, but there was a lot of chatter social media. There was a lot of very, we'll say, loose data being released in pre-prints with very non-standard endpoints and experimental therapies that was being touted in the lay press. And so it was a really confusing time, honestly.

And so we did the best we could to rough together the best information that we had. And I think that our approach from a drug treatment stance has always been, don't just do something. Stand there. At times where there wasn't enough data, we had to just really rely on the skill and the knowledge of our critical care providers and the people that were doing the hands-on patient management to say, you manage ARDS the way that you manage ARDS. And from a therapeutic standpoint there's not a lot of great options at this point in time.

So there were a few experimental therapies included initially or sort of off-label therapies, hydroxychloroquine and lopinavir were on that document in very specific scenarios on inpatient management initially. As time and literature evolved, I think what we've been able to do is migrate that over to AME. And so that guideline is now available in AME. It has a really wide array of information, including information from pulmonology and cardiology and pediatrics and lots of different specialty groups.

So how we've managed to maintain this, most recently, is the infectious disease division formed our COVID-19 rapid literature review task force that assigned various COVID topics to different groups of individuals so that no one person or even one group was responsible for keeping up to date with testing and transmission and post exposure prophylaxis and treatment and all these things.

And so I was sat on the therapeutic group. And once we were initially able to get our therapeutic recommendations honed down to where they, I think, relatively sit today after the remdesivir Act One was released and some of the hydroxychloroquine and lopinavir, retonivir data has been released disproving those therapies. What's largely happens at this point is working with the current center as they index a lot of the publications, as well as the librarian.

We review all of the COVID-19 therapeutic literature that's produced. And then we sit together as a treatment team, and we decide, does the data that's most recently produced lend to any changes in the existing guideline?

And so twice a week we get emails from the librarian, and we assess the literature that's coming out to say, does this have the strength of evidence? Does it have the endpoints we need? Does it have the-- all these factors we would consider that this would be a practice changing study. And so at this point that's the ongoing process for how the AME module and the treatment guideline recommendations get changed [INAUDIBLE] through that phase.

And just also to piggyback on Kirstin's and the question you asked about interfacing with other institutions. I think it's a little-- you have to be a little bit careful about this. Because it's not all that different than the early report of 21 patients who got [INAUDIBLE], and there was no control group. And so word of mouth has even a little bit looser, and so we have to be careful with how we take clinical recommendations from word of mouth and apply them.

So I totally agree with what Kirstin said, and that's why I think we have to look to the structures that have been in place for how do we do rapid literature review? How do we do tele-rounding, and what are the structures that we set up in order to allow this to change quickly? Because it's constantly morphing.

And so I think rather than looking to their experience with specific therapeutics or specific interventions, we've really been looking to each other in the health community for, how do we assess the literature? How do we set up rounding? How do we set these structures up in order to best care for patients?

LEE SKRUPSKY: Excellent points, Ryan. All right. So I think we'll jump to a question. We've had a few likes on this one, and I'm sure it's on top of everybody's mind, especially in critical care.

So with the release of the recovery trial looking at dexemethasone and these patients, what is the panel's thoughts on the use of dexemethasone in COVID patients, given the recent preprint findings? So both Kirstin, if you want to start, and Brad, certainly if you have comments as well either which way.

KIRSTIN KOODA: So this is another example of the news heard about something and spread it all over the world before there was any data out. So I was happy that at least the preprint got released so that we could look at it. And our job is made a little bit harder by the fact that the NIH came out and said that they advocate for this therapy.

So personally, I think it's difficult, because we can't necessarily say that their patients are the same as our patients. Their mortality rates were between 30% and 40% in this trial. Ours here, I believe, are less than 10%, right, Brad? So it's hard for me to say dexemethasone should be used in every critically ill patient, because we don't have the same overwhelmed end point that these other people are seeing.

And it's hard as well because with the recent study that came out in February about the potential benefit of dexemethasone in ARDS seems like there is some argument that there is a signal that it could be useful. But the other concern is that similar to influenza, steroids in influenza potentially prolong viral replication. So we're really stuck in a rock and a hard place on how to use this.

And if critical care is still trying to decide what their standardized approach is going to be, personally, I think not using it in every patient. And I really want to see the peer reviewed version of the paper to see what other kind of commentary that they have on it.

LEE SKRUPSKY: A follow up maybe to think about would maybe be, what would be some populations or considerations that would either steer you toward favoring the use versus less favorable considerations where you'd want to avoid the use?

BRADLEY PETERS: So when I think about some of the people that I'd potentially be more favorable for using it, I'd definitely look at the study. Because I know they looked at those who did not need oxygen. Those who needed oxygen mostly ended up getting intubated. And thus far the only positive signals were in the ones that required oxygen and the ones that required intubation.

I'm hoping that we don't-- because the news spread this because it got out not through necessarily the full peer-reviewed process and whatnot, that people are just going to grab on to this and say, I got COVID. I'm sitting at home. I think I need dexemethasone. Because I don't think that's going to do us any favors.

Beyond that, I think we can-- those are the main ones that I think I can see. I don't-- have you-- but this has just come out so quickly that I haven't really thought about some of the other main population.

KIRSTIN KOODA: Yeah. And I'll talk a bit more about some of the lab monitoring that we're doing to help make the decisions, because [INAUDIBLE] was talking to me earlier about looking at elevated CRPs as a trigger, which is certainly reasonable. There is a bad inflammatory state with COVID. We know that-- the problem is that all critically ill patients have inflammatory states.

All of them have elevated D-dimers. All have elevated CRPs. And historically, we've tried to use those markers as a measure of severity of illness and it hasn't really panned out in a way that lets you choose a treatment that will make that person better. .

That said, I think going along with what Brad said, it is that person who is more ill. We cannot stabilize with our standard ARDS care. Early on in the course before they hit that [INAUDIBLE] stage where you still potentially can impact the outcome, who's got a ragingly high CRP, I think I'd be more willing to use it in that person.

Unfortunately, that's not really backed up by the evidence that we currently have. This is more of an opinion statement than anything that's reasonable. But we just-- we don't know enough yet, and we need to see the whole trial before I think we make a strong treatment decision for all patients.

CHRISTINA RIVERA: I'll piggyback, too, and say in our immunocompromised population, Chris, what do you think about use of dexemethasone? And then also, Laura, in pediatrics?

CHRIS ARENDT: Yeah. So in our immunocompromised population, we know that in patients who are-- who've received lung transplants, steroid is a good thing. We also know, though, that in acute viral illness, steroid is not. And so we have to kind of weight what is the risk benefit and hopefully lend ourselves more towards the benefit on that side of the curve whenever we can.

I do know that there have been some small studies looking at COVID in transplant, primarily within the kidney population, as being probably the more prolific of the organ groups who've been out there. And they're finding that they can't necessarily say that just because you're on immunosuppressants you have worse disease. And so we don't know, for a fact, that if you're a transplant, you're going to have more or less of a response to the disease or to the therapies.

So much has been said by Brad and Kirstin here that we just don't have enough evidence to push us to the direction of saying that everybody should be on dexemethasone, or everybody who has a transplant requires some additional invasive strategy.

LAURA DINNES: And for pediatrics, I would have to say we're kind of-- this whole time have been sort of following the suit of the adults. And so our stance right now is that there really isn't any data to suggest we should use it in every patient beyond what Brad said. And so that's kind of what the plan is.

If needed, the only other indication I could potentially see it being used is-- we haven't seen in a while, but the vaping lung injury. If that ever comes up with the COVID, that could be one indication in which I could see them using that in pediatric patients. But like I said, we have really been seeing that as much as of late.

Otherwise, I don't think that we'll be using it much, similarly to the other medications we've been using throughout this whole time. I mean dexemethasone, we use in children all the time, but we don't know what dose-- I mean they recommended a specific dose from that recovery trial, but what dose do we use in pediatric patients? So that's ultimately what we don't know either.

RYAN STEVENS: So one other thing that I think is worth mentioning here is that when you're talking about therapeutics and you're talking about COVID in general, you're talking about two different phases of illness. You have a viral phase and you have the immune hyperactivation phase that may progress or may be accompanied by the [INAUDIBLE] sort of syndromes.

And I think when you're looking at the agents in the therapeutics that are being used, you also have to look at what stage the patient's in. And so when we're looking at like steroids and tempering an immune response in a hyperimmune activation, then it would make sense that those that are most critically ill are sort of in that phase would be most likely to derive benefit. And thereby, they may not be appropriate for someone that's early on.

And so that's where broadly applying these therapeutics and saying, well, this-- we should give everyone with COVID dexemethasone is probably not appropriate, because not everyone will progressed to a hyperactivation of the immune phase.

So that's also similar with the antivirals. When you look at some of the antiviral data, even with the other coronaviruses, MERS and SARS-CoV-1, there are some signals that when the antivirals are started earlier at the peak of viral replication that they may be associated with the better outcomes. And so in my mind, I guess, as this has progressed, and, again, sort of an opinion, but I think I blunt the agents into the antivirals and into the immune agents and also timed them appropriately with the phase of the illness that we're seeing.

And so this idea that we can just generally apply all therapeutics across all patients with COVID is not necessarily something that I think is going to shake out in the end. So it makes sense what we're seeing with the recovery trial as well as what we're seeing in the Act One with remdesivir.

LEE SKRUPSKY: Yeah. Thank you, Ryan. I think you just nicely summarized the last several decades of sepsis research and ARDS research and the conundrum that we face everyday, right? In that to do large trials, you have to broaden those criteria, but then you enroll a pretty broad population. And we don't have great ways to identify those or markers of those processes that at least logically would make us think that those may be more likely to benefit.

CHRIS ARENDT: And I'd like to piggyback on that. And then, of course, as part of the complication because so much of this is being done on the guise, on the shirt tails of being research, we're saying, you can be on one therapy but not the other because you're going to confound it. And so when in reality, we probably need this natural step of we go from one therapeutic to the next.

And so really what we're doing is a lot of single drug studies that aren't necessarily giving us the picture for the clinical treatment of the patient, the actual therapeutic treatment, but merely just this particular moment of a syndrome where that drug may or may not be appropriate.

LEE SKRUPSKY: And I don't know if that sparked any thoughts or comments for you.

ANNA BARTOO: No. I was just going to say out of the multiple clinical trials we're doing at Mayo, dexemethasone is not one of them.

[LAUGHING]

LEE SKRUPSKY: [INAUDIBLE] ask a question for Anna here. We've mentioned that the pace of getting these trials up and running and participating has taken on a new path, I guess, or speed. Can you comment on any of the process changes or challenges that you and your team have encountered throughout this process so far?

ANNA BARTOO: Sure. Thanks, Lee. So it was kind of interesting, because about probably seven or eight years ago, the institution really looked at the time that it took to get a clinical trial activated at Mayo and said, what can we do to make this faster? So they developed this program called ACT, Accelerated Clinical Trial, and they looked at processes that they could put in series rather than parallel and things that could be happening at the same time.

But under the ACT, the time to clinical trial activation is still 65 days. So 65 days is still considered a fast activation of clinical trials.

With COVID-19, I think within the first week we had four clinical trials up and running. And so really it was incredible to be part of this team to see the way the Mayo Clinic, as a whole, operationalized to speed this up.

And because it's interesting-- I think the first thing I learned when I entered pharmacy school was I heard all about teamwork and being part of the health care team, right? And with clinical trials there are team members that you don't even know about, right?

There's the people doing the coding coverage analysis and the finance. There's the IRB. There's the protocol development specialist-- liaison, being a liaison with the study's sponsor.

And so it was kind of interesting because actually in the case of remdesivir we were ready before Gilead was, right? Like it got in a page on a Thursday afternoon saying we're having the site initiation visit via teleconference at 3:00. Can you be there? And it was like, of course.