Thanks, Ken, and thank everybody for being here. As Craig said, I've been a panel member of the NIH COVID Guidelines. I've also been a surviving sepsis campaign panelist and a senior medical advisor to BARDA. I guess that's all come out already. I have no conflicts of interest. These are objectives for today, and I just want you to know that this will be through the lens of sepsis and surviving sepsis guidelines through the lens of COVID-19 and COVID-19 guidelines. So, here's a question you may ask yourself as a clinician, which is, why is every agent authorized by FDA not recommended by NIH guidelines? And conversely, why are there agents recommended by the NIH guidelines that aren't approved by FDA for the purpose, specifically COVID-19? So, we're going to start by looking at the FDA's role, and I don't want to put words in anyone's mouth, but this is directly from the USA.gov website. The FDA is there, and they're responsible for protecting public health by assuring safety, efficacy, and security of the medical products we use, along with other things. Now, if you want a drug approved by the FDA, first you have to go after approval for a specific condition. There is a thorough evaluation involving clinical studies and involving an expert panel at the FDA for review, and you have to demonstrate proven efficacy and proven safety in order to get a FDA label for your drug. What the FDA does not do specifically is the FDA doesn't provide advice as to which agent is the best advice or the best agent for treating a given condition, and that's really where it falls to a guideline. FDA has a particular role in pandemic emergencies in that they can authorize unapproved medical products or they can authorize unapproved uses of already approved medical products. They have to meet these kind of criteria. It has to be a serious or life-threatening disease. There has to be shown evidence of effectiveness, and the evidence actually doesn't even have to all be human studies. Evidence is acceptable for both efficacy and safety from animal studies even, because we're talking about that there are no alternatives, and the FDA just is required to do a risk-benefit analysis in that case and determine whether this is useful. So let's turn to you and me here for a moment as clinicians, though. So we look at a drug in a different way. The first look is a drug available to me to use, which means it's been approved by FDA for something some time, and do I think it's going to be useful to this patient in this situation, but honestly, how often do you ask, is it approved for this indication? I'm going to prove to you, I hope, that there are a lot of times when you don't, or there's at least one time. There's a drug called epinephrine, and this from the FDA website are the indications for which it is approved. So the first one is increased mean arterial blood pressure and septic shock, check, okay, we know about that. Second one is emergency treatment of allergic reactions including anaphylaxis, check, we know about that. Third one, induction and maintenance of pupil dilation for ocular surgery, well, I've never done that, I don't know if you have or not, but some people do, okay, but did you ever stop to think, whenever you're treating this particular condition here, that this isn't FDA approved, so why do you do it? Because you're not seeking FDA approval, because you are a licensed independent practitioner capable of reading the medical evidence, and you know that epinephrine is useful in this circumstance. Okay, so that's us as clinicians. Here's some more circumstances rather similar to that, in fact, I'm showing an array of agents that were literally used for COVID-19. They were all FDA approved for another condition before COVID-19, and here in this column, you can see docs used them, yes, APPs as well, by the way. And there's an array of things that happened here, like here's one that got an EUA, but then it was withdrawn about three months later, was never recommended in the guidelines, but people used it. Here's one that was never given an EUA, was never recommended in guidelines, but people used it. Here's one we just talked about, did get an EUA, is in the guidelines, people did use it. This one not only got an EUA, but ultimately got FDA approval, was in the guidelines, people used, and then dexamethasone, fascinatingly, never got an EUA, never got approved by FDA for COVID-19, but was in the guidelines and has been used a lot, okay? So these are the ways that we use drugs once they are available in the marketplace. So on the one hand, we've got FDA approval or emergency use authorization, and on the other hand, we've got guidelines and their recommendations. So really, why do guidelines exist? Let's nail that down very quickly. Guidelines actually do exist to recommend the most appropriate treatments based on the best available evidence, so that's why we have them. So I'm going to take a stop here very quickly on a PICO question. What is that? When we make a guideline, we look at questions, we look at what's going to be useful in this lens. We say, what patient is it that we want to treat? What is the intervention we want to use? What are we comparing it with, and what's the outcome? And we hopefully choose outcomes that are important to patients, so that when we're making a guideline, we could ask the question, should we use steroids to treat COVID-19? Or to ask a better question, should we treat people that have COVID-19 respiratory failure on a vet? Those are the patients. Should we treat them with dexamethasone compared to no dexamethasone? And what's our allowable outcome? Improved survival. Okay, now that's a good PICO question. That's how we put together a guideline. There are different ways to approach this. Surviving sepsis approaches it via a very sophisticated mean using GRADE techniques, which you can see what that stands for over here. So, several steps, evidence tables, but the bottom line is it comes out with a recommendation that tells you the strength of the recommendation and the strength of the evidence that supports the recommendation. NIH does it a little bit differently. They've been making HIV guidelines for 30 years, and the same techniques were ported over to COVID-19. But still, the bottom line is a strength of the recommendation, in this case, three different strengths, and a basis of evidence. Okay, so now I'm going to pose a little hypothetical question to you, because it was fairly, frankly, I found it easier in the beginning because there was nothing, and then there was something, so it was easy to look at. But then, as the pandemic proceeds, so here's the hypothetical question. Here are the current recommendations for people that are hospitalized and need high-flow nasal cannula oxygen or noninvasive ventilation, and what we say is that they should all get dexamethasone, and there's high level of evidence supporting that, level one evidence. They should also get an additional immunomodulating agent, and there's a high level of evidence supporting baricitinib in multiple studies, lower levels of evidence supporting these other things. So the question to you is a new study is published today, has about 500 patients in it. It compares people who are on dexamethasone. It compares the new immunomodulator versus placebo. It's effective. It receives an EUA from the FDA. As it turns out, only about 5% of the people in the study have received baricitinib, which we recommend with a high level of evidence. So what do you do with this drug? Where do you slot it in? I'm not going to tell you what I would do. I want you to think what would you do knowing we have high-level treatments we already recommend. How do we slot this into a guideline? So I'm going to tip my hat here to Dr. Coopersmith, because he and I have reached the same conclusion on one thing. So what are all those previous data good for? So I asked this gentleman, Edwin Starr, who put out the song War in 1970, and this is what he said, huh, absolutely nothing. Good God, y'all. And so I think we agree. And if you get that reference, you're either an old geezer like me or you're a music aficionado. So thank you. But let me give you an example. Let's look at dexamethasone for a second. Now COVID-19 in the ICU quite clearly represents life-threatening organ dysfunction due to a dysregulated host response to infection, meaning it represents sepsis. So should we now turn around with our new surviving sepsis guidelines and put it in the guideline? Well, haven't we kind of tried that with roughly equivalent steroid doses of hydrocortisone? So the best we can say is that we may have found a defined subset of sepsis that responds to dexamethasone. So when the new pandemic comes, we start almost from ground zero. Just want to point this out. This is a guideline that I thought was truly useful. Surviving sepsis put this out very early in the pandemic. And basically what it said was, we may not know COVID-19, but we know critical care. And let's not forget that. And in the main, this guideline was excellent. The one thing, interestingly, where they stuck their neck out, the one thing where they might have missed a little bit, was we suggest against the routine use of systemic corticosteroids. So I find that a little piece of irony there. So to conclude, a guideline requires solid clinical evidence of efficacy and safety for the specific agent and the specific patient. It's a higher bar than an EUA. It's a different bar than FDA approval. Standards are appropriate, and the comparator actually changes through the course of a pandemic. So basically, a guideline requires as much rigor as we can apply in the new circumstance. Thanks.

COVID-19 treatments

FDA authorization

NIH guidelines

off-label drug use

pandemic evidence