Narrator - Dr. Abel  00:00
Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions.

Narrator - ?  00:11
This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy.

Narrator - Dr. Abel  00:17
This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider.

Narrator - ?  00:27
And now on to the show.

Dr. Sean Kane  00:32
Welcome to HelixTalk episode, 124 I'm your co host, Dr. Kane. Unfortunately, Dr. Patel is not with us today, but she will be back with our next episode. So I am flying solo today, and the title of today's episode is the ABCs of EUAs understanding FDA emergency use authorizations. So this has definitely been in the news recently with two newly approved covid 19 vaccines. But as we'll talk about in today's episode, there's actually a number of other therapies that have undergone this emergency use authorization from the FDA. So we're going to talk about what that is. And as a healthcare provider, how can you stay up to date on this very fast moving market of these emergency use authorization medications? So to kind of set the tone for today's episode, I want you to think about sitting back, relaxing, having your pandemic eggnog during the holiday season and during your zoom call with your family or friends. Uncle Bill says, How safe is that covid 19 vaccine? And you ask yourself, what is the best way to answer that question? What is the best resource to figure out the safety of that vaccine? Or maybe you're wrapping up the tasks at a hospital that you work at, and before you go home, a physician, let's say Dr. Strangelove, pops his head into your office and says, What's this new medication I heard about, called casirivimab with imdevimab. How does it work? And does it work at all? And again, asking yourself the question, how can you find more information about this combination monoclonal antibody therapy that was approved under this emergency use authorization process? What is the right way to go about understanding the EUA process and then also getting more information about these EUA drugs? Now, in true NPR fashion, I wanted to just clarify that this episode is recorded on November 21 2020 so things may have changed by the time you listen to this which is going to go live January 5, 2021 so hello from 2020 hopefully 2021 is already better, but things may have changed in terms of this emergency use authorization process, or other therapies that have been approved, especially for covid 19. So before we get to some of those covid 19 specific therapies, I think it's worth talking about what is an emergency use authorization or an EUA now, in times of an emergency, and there's a very specific term for that, the FDA can grant access to drugs, devices or biologic products, and this granting is done through the secretary of the Health and Human Services this process, this EUA process, is actually defined in the FD&C Act in Section 564 so if you want to nerd out on the actual rules and regulations of this process, you can go to section 564, to learn more about it. Now, during this approval process, there's kind of two pathways that a product can go through. One is that it is a non approved entity, non approved product, so it's never been approved for anything ever, and it's called an unapproved product if it does go through the EUA process. Now, the other pathway is when a drug, device or biologic product is already on the market and FDA approved for something different, and the EUA covers some new indication, some new disease state that it's used to treat for, and in that case, it's called an unapproved use of an approved product. So really two pathways, something that's never been approved, something that has already been approved, but we're trying to use it for something that is a new indication for it now, as the name would suggest emergency use authorization, this is only for legitimate emergencies, and there's only three departments in the US government that can actually call it an emergency. So this is either declared as an emergency by the Department of Homeland Security or the Department of Defense, and usually that would be for like a bioterrorism or chemical threat, or the Department of Health and Human Services. HHS can declare an emergency, and this would typically be more for a public health emergency, like with covid 19. Now, when the emergency is declared, the intent of anything approved under that in terms of the EUA approval process, the intent is that these EUAs really should not last more than a year during that time, the intent is that the manufacturer of a product is seeking full FD. Approval. And in fact, if it takes more than a year and that EUA is active for more than a year, there actually has to be formal writing to describe why the full approval process has not occurred yet that the EUA is still active. So one key concept here is that EUAs are for short term, typically less than a year, while a full approval is in the works in terms of what criteria the FDA uses to authorize an emergency use product. Obviously, it has to be an emergency. So this is a disease or condition that is serious or life threatening, and based on the available data that is provided by the manufacturer of the product, the product may be effective to diagnose, treat, prevent disease, and the known or potential benefits have to outweigh the known or potential risks of that product. And then finally, the last criteria is that there is no adequate, approved and available alternative to treat the condition. So thinking about covid 19 for a second, it's definitely a serious or life threatening condition. Based on the available data. For some of these products, they were able to demonstrate that they probably have efficacy to diagnose, treat or prevent covid 19. And for many of them, they were able to demonstrate that the known or potential benefits outweigh the known or potential risks. And because there are very few therapies for covid 19. Generally, they were able to demonstrate that there weren't appropriate alternatives that were already approved on the market. Now, if you think about it, why does the EUA process exist in the first place? Obviously, it's for an emergency. But why do we need it? The biggest reason is that, depending on the nature of the emergency, covid 19 being the obvious example here is that sometimes we don't have enough time, and we have an immediate need to have a treatment or a therapy for a given condition. So if you think about vaccines, for example, the current two vaccines, the Pfizer and the moderna vaccines, those had a median follow up period of about two months. So in general, people in the studies had two months of follow up to ascertain the durability of their immune response. Now, for many other vaccine trials, this follow up period would go 1218, months, maybe even longer, up to several years, to assess the durability of that immune response and the efficacy over time of that immune response. But in the case of these covid 19 vaccines, if we waited two or more years, really there's no, no role for the hopefully no role for those vaccines anymore. We want them as soon as possible, because we have an emergent, immediate need for them now. And that's really the perfect example of when an emergency use authorization could potentially be useful in a situation like this. Now, obviously, EUAs are something that is in the news a lot right now, with two new vaccines, many other therapeutic products that are being approved through the EUA for covid 19. But you might not know that there are actually a number of other EUAs that have been issued historically, besides covid 19. So if we go all the way back to 2008 doxycycline was actually approved under the EUA process for the treatment of inhalational anthrax, so more of a biological terrorism type indication in 2009 the FDA had an EUA for three different antivirals for H1N1. So this covered peramavir, oseltamivir and zanamivir. In 2013 you know, it's not just drugs that get this UA process, but also testing equipment, devices, things like that. In 2013 the MERS cov test was approved through an EUA. 2015 an Ebola test was approved. 2016 a Zika test was approved. So it's not just covid 19, although obviously, given the scope and nature of covid 19, we're seeing a lot more with that versus some of these other emergencies historically. But it's important to note that it's not just covid 19 that put EUAs on the map. In terms of the EUA itself, there are some requirements set out by the FDA through section 564, so one is that healthcare providers and patients or recipients have to be informed of certain things. So one, everyone has to know that it's not a formal FDA approval, but it's an emergency use authorization approval, which means that it's not to the same degree or extent as a full FDA approval for both healthcare providers and patients, they have to know about known and potential risks and benefits of the therapy or the product. They have to know whether there are alternative options and what those alternative option benefits and risks are. And then, for patients or recipients of a product, they have to have the option to accept or refuse the product, after hearing more about the benefits and risks. And then finally, for all of these EUAs, there has to be an ability to monitor and report adverse events associated with the product. That makes sense, that if we potentially don't have enough safety data, as we normally would like to but because of an emergency. See, we wanted to get that product out as soon as possible, there needs to be a mechanism by which, if a product is not safe, that we have the ability to monitor for that adverse effect profile and potentially pull it off the market, pull it out of the EUA process if there's harm being done. Now we will talk about remdesivir in the vaccines in a second, but in looking through the FDA website, which is linked in our show notes at episode 124, HelixTalk.com there's actually a bunch of other things out there besides remdesivir and covid 19 that have been approved for covid 19 under this UA process, for example, there are continuous renal replacement therapy products or CRT products. There's a double concentrated propofol, so 2% instead of our traditional 1% propofol, there's convalescent plasma that we'll talk about in a little bit. And then there's a number of monoclonal antibodies that are out there, like bamlanivimab. There's also the combination of casirivimab plus imdevimab. And then finally, another product that is already FDA approved, but is one of those approved products for an unapproved indication, baricitinib, in combination with remdesivir. All of these have EUAs, where you can see them on the FDA website and get more information about them. So if you were to do that, if you were to go to the FDA website, what kind of information might you find? So as a healthcare provider. This is obviously really important to have readily available access to as much information about these new products as possible. So you'll find a fact sheet for healthcare providers from the FDA. So this is very similar in structure to a package insert. Kind of has a cliff notes version and then kind of a full package insert after that. And the structure is very similar to that package insert. It should be fairly familiar if you've seen a package insert before. Now, again, this is available under the FDA EUA website, which is linked in our show notes. But also, if you go to daily Med, which is a common resource to look up package inserts approved by the FDA, you'll be able to see it there as well. In terms of this fact sheet for healthcare providers, this package insert. When you do look at it on daily Med, it will say, in the marketing status unapproved drug other which means that it's not an FDA approved drug, even though it's in daily med. And you can find a package insert looking document on the website, on the FDA website, you'll also see a fact sheet for recipients and caregivers. This is essentially a patient insert, where it has information for patients and patient friendly language also has a number of other languages besides English that a patient would be able to see and then probably the best part about this is, on the FDA website, you'll be able to see other documents that healthcare providers are going to find useful. So for example, they'll have frequently asked questions that's pretty useful if you're getting a lot of questions about these products. Probably my favorite thing that I was able to come across is what's called a decision memorandum, which sounds very fancy, but it's basically a summary of the evidence, the discussion about that evidence, and even the meeting minutes from the FDA when they evaluated the EUA for a given product. So if we use remdesivir as an example, and to be clear, we are not talking about remdesivir as a full podcast episode, but just to use that as an example, the FDA issued an EUA for remdesivir on May 1 2020, and appropriately, the manufacturer applied for FDA approval, and they actually got it on October 22 2020 so early in May, they finally got a full FDA approval for Veklury on October 22 and that approval was for patients that were 12 years of age or older, and they had to be 40 kilograms or heavier, and they had to have COVID-19 requiring hospitalization. And what I love about this is that it really shows how the EUA process is supposed to work. We're able to have access to remdesivir Early on, the manufacturer went through the approval process, and in a fairly short period of time, we were able to get a full FDA approval of that medication. What's interesting, though, is that if you go to the EUA website, you'll still see remdesivir There. And the reason for that is that the EUA now it covers those that weigh less than 40 kilograms. So it's actually three and a half to 40 kilograms is what the EUA covers. It also covers younger children, anyone less than 12 years of age. So the EUA is actually still active because they didn't do an adequate RCT on this kind of pediatric group. So the UA is active for those pediatric patients, but the full FDA approval is active for everyone else that meets that criteria. Another example would be the Pfizer biontech covid 19 vaccine. And again, this is absolutely not a full podcast about the vaccine. And obviously there's now a second vaccine, the moderna vaccine. But using this as an example to kind of emphasize a couple points about the EUA process, I think is relevant. So at the time that the Pfizer vaccine was approved through the the EUA process, the New England Journal of Medicine published their preliminary phase three results, and again, they want to study these patients all the way out to 18 months, but they only had two months worth of data for these patients. So this is a preliminary report, and it's 13 pages in PDF form. If you go to the supplement, it's a 12 page supplement, but really only four pages have actual data. So essentially, you have a 13 page manuscript plus four pages of tables within the supplement. Now, if you go to the EUA document, which is on the FDA website, if you go to that fact sheet for healthcare providers, that package insert like document, it's 29 pages, fairly small font, so there's a lot more in there than what you're going to find in that New England Journal of Medicine publication. In addition to that, if you looked at the fact sheet for recipients and caregivers, it's six pages, but it has a bunch of really important stuff in there that patients might find helpful. As an example, for the healthcare provider sheet, it has things related to storage. So how long is the vaccine good in the fridge, five days. And what about at room temperature? So it takes 30 minutes to thaw. If it's undiluted, you have to use it within two hours at room temperature. After you dilute it, you're supposed to start in the fridge for up to six hours. All of that information is in that package insert for healthcare providers, which is obviously really important given the unique storage requirements of the vaccine. Now, again, probably my favorite part of what the FDA offers is this memorandum. Again, this very fancy term for a detailed summary of the FDA review and the approval of, in this case, the Pfizer vaccine. Now that memorandum is 57 pages, and it nicely has a very short executive summary, if you don't want to read all 57 pages. But they also have a lot of really nice tables for of data, and this is great for a quick review if you're looking for something specific. So you're going to see things like baseline characteristics, results of efficacy, subgroup analysis, safety results, things like that, you're going to have more tables in this memorandum than what you got from the New England Journal of Medicine article. And in New England, some of those data are presented as graphs or graphical representations, where you can't get the actual data versus in this memorandum, everything is in table format, just numbers, so you can get the true numbers exactly at how it was reported to the FDA. Just to highlight a couple cool things that you're going to find in that memorandum from the Pfizer vaccine, it mentions Bell's Palsy, which is a facial paralysis. So there were four cases versus zero cases. The FDA felt that four cases was still at a normal surveillance rate of Bell's Palsy, but they recommended surveillance to make sure that this doesn't become a bigger deal. And Bell's palsy was never mentioned in the New England article. And if you're curious to moderna vaccine, it was three episodes with the vaccine versus one episode of Bell's palsy with the placebo. So again, kind of background noise, but it's interesting stuff, and if you want to dive deeper into it, this is the place to go. The FDA memorandum also talks about stuff that happened after the New England Journal article was published. So for example, there are two cases of anaphylactic reactions in the UK. This occurred outside of a clinical trial. Both of these patients had a history of anaphylaxis, but they weren't specifically allergic to an ingredient within the vaccine itself. So again, you wouldn't get that from the New England article, because at the time, we didn't know about those events, because it hadn't occurred at the time that they wrote the manuscript. Also, you can see in the memorandum that the manufacturer is planning for an 18 month follow up period. They also plan to offer the vaccine to placebo patients. And a really neat, neat area of that memorandum was the unknown benefits and data gaps section. This is kind of the cheat sheet for anyone who wants to know, what do we not know or what are big questions that are still looming about, in this case, the vaccine, but this section could be relevant for any of the medications. So one thing they mentioned is duration of protection, so we've only followed these patients for two months, so that's a big question mark. Another question mark is efficacy and safety in certain patients. So immunocompromised patients were under studied. Those that were less than 16 years old and pregnant were not studied at all. The study was underpowered to evaluate a mortality benefit, so we don't really know how many patients need to receive a vaccine for one patient to not die of covid 19. And we also don't know the efficacy of preventing transmission of the virus either. So again, this is not an episode about the vaccine itself, but all of these really cool nuggets of knowledge and questions are built within this memorandum and these other documents that the FDA provides to healthcare providers. And perhaps the most interesting thing was the VRBPAC meeting summary. So this was the meeting summary of the small group that got together to make a recommendation about the emergency use authorization. It's basically the meeting minutes, and you can. Actually see specific issues that were brought up during the meeting. You can see how everyone voted. So the actual vote was 17 people said yes. They thought that this should be an emergency use authorization. Four people said no, and one abstained. So again, from a clinical standpoint, probably not relevant, but from kind of an interesting standpoint, I think it's definitely there in terms of something that you might find interesting to read. The other interesting thing about this process is that just because an EUA happens doesn't mean that that EUA is guaranteed to eventually result in a full FDA approval. We actually have one clear example of this, and I would suspect another example coming soon. So the clear example of this is hydroxychloroquine or Chloroquine. This was approved as an EUA on March 28 so the actual emergency was declared February 4, the EUA for hydroxychloroquine and Chloroquine was approved March 28 and then, actually in June, middle of June, the FDA actually removed. They revoked the emergency use authorization for both of these medications, concluding that it is unlikely to be effective and may cause serious cardiac side effects. So they said the benefits no longer outweigh the risks. And the EUA was revoked. And you can actually read the revocation letter. They go into a lot of detail about literature that came out after the original EUA, and the rationale for removing the EUA. And I think that this is really, really cool example of, again, the process working. As we get more data, we conclude that we probably shouldn't have that as an EUA. What's also interesting is that hydroxychloroquine, although the EUA was revoked, it's still in the market for other FDA approved uses, so malaria, lupus, rheumatoid arthritis, but if you look at that EUA, you'll see a big revoked watermark on the document indicating that it's no longer active. And if you go back and kind of wonder, well, you know what? What amount of data was it that really got it revoked? It's fascinating that the initial EUA was based on, quote, limited in vitro and anecdotal clinical data in case series. End, quote. So again, we're not having a podcast specifically on covid 19 therapies, but for the most part, I think most healthcare providers would not consider that adequate evidence to support an EUA, but it's good that that was eventually revoked, potentially another similar issues I believe may happen with convalescent plasma. So the EUA for convalescent plasma happened on August 23 2020, and it was approved based on non peer reviewed, open label, observational, multi centered data. So basically, these are a large cohort of patients. Everyone got convalescent plasma. So there was no comparison arm, really. The original study was intended to look at convalescent plasma safety as opposed to efficacy. Because of the observational study design, we're worried about selection bias, a lack of a control group, confounders, things like that. And actually, there was a New England Journal of Medicine study published in November called the plasma AR study that showed no benefit. And this was a randomized controlled trial, no benefit of convalescent plasma. So on the basis of really not great quality data that got it approved initially and now, good randomized control data showing that there's probably no benefit, I would suspect that convalescent plasma may be another scenario in which the EUA may be revoked because of a lack of benefit for the therapy. Let's go back to our original situation. Uncle Bill through Zoom is asking about covid 19 vaccine safety. So if you were to go to the emergency use authorization, prescribing information, again, linked on our show notes, or even on daily Med, if you go to Section six, Section six is called overall safety summary. So you're going to see all of the information from the FDA about that safety profile. And you could even go in the memorandum and get even more data about things like Bell's palsy that may not have made it into the prescribing information. If we go back to Dr. Strangelove asking about this combination monoclonal antibody product, how it works and how effective it is, this was casirivimab plus imdevimab. Section 14 called Clinical Pharmacology is going to talk about the mechanism of action. Section 18, titled clinical trial results in supporting data that's going to talk about the efficacy of the medication, and potentially, depending on the nature of the approval, you might also be interested in Section 17, which is animal pharmacologic and efficacy data. So you're going to find a lot of really good information. This is probably going to be your best source of information if you really want to dig deep into some of the these EUAs, especially for drug therapies. So where to go from here? So as we wrap up 2020 and start 2021 I can almost guarantee you we're going to see more emergency use authorization approvals and the. United States for covid 19 specifically. And the reason that that's relevant is that all healthcare providers who treat covid 19 patients are going to need to stay up to date with these new therapies, how they work, what they interact with, their safety profile, things like that. These EUA documents are going to be one of the best resources to be able to do that, especially because many of these EUAs don't necessarily have a phase three preliminary clinical trial publication in New England Journal of Medicine. That's where many healthcare providers are getting their data right now, is from a journal publication, but some of them aren't published in a journal, and you know that 10 page manuscript, if it was published, may not have all of the data that you might like to see, and going to that FDA website with the EUAs is going to be the best place to get a lot more data. So if it isn't clear already, the number one best source of information for these EUAs is going to be the FDA website. You can get the prescribing information through daily med. It's kind of a convenient way to do it. But if you want the prescribing information, the patient information, the frequently asked questions, the memorandum, the meeting notes, you're going to want to go to the FDA EUA website to get all of that data. So to wrap up, today's podcast episode, couple key points. Number one, an emergency use authorization, or EUA, is a special type of FDA approval only used in times of emergency in which a product may be effective to diagnose, treat or prevent a disease, the known or potential benefits outweigh the risks, and there are no adequate alternatives to treat the disease. Number two, all drug therapy EUAs are approved in conjunction with an EUA prescribing information document, along with many other very useful documents, healthcare providers should be looking at these documents to learn about these new therapies and stay updated. Number three, not all EUAs are going to result in a full FDA approval. And in fact, in the case of hydroxychloroquine and Chloroquine, the FDA actually revoked those EUAs due to a lack of benefit and potential risk of harm. And number four, a drug can be FDA approved on the market for a given indication, and then also have an EA for an unapproved indication. This is called an unapproved use of an approved product. Hydroxychloroquine is a great example of that for malaria, lupus, rheumatoid arthritis, where it maintains those FDA approved indications, but the EUA for COVID-19 has now been removed, and that distinction is actually really important. You're going to get a lot of clinical pearls like that through the FDA website. So that wraps up today's episode quite nicely. If you'd like to learn more information about the UA process or go to the FDA website, you can go to our show notes at HelixTalk.com episode 124, read all about that. We're also on Twitter at HelixTalk. We love the five star reviews in iTunes, so keep those coming that helps us climb those rankings in iTunes so that other healthcare providers are more able to find our podcast. So with that, I'm Dr. Kane, and in the words of Dr. Patel, study hard.

Narrator - Dr. Abel  27:58
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Narrator - ?  28:09
to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.