 the video on both CSIS website in the next day as well as SmartGlobalHealth.org which is the website for our micro website for our global health program. We come to this subject around diagnostics for a couple of reasons and we'll hear much more about this from our speakers in a moment. We've come to it as part of a broader set of work that we've done focused on vaccines, focusing on the emergency operational response, traveling to the region and talking to people about what has transpired during the crisis and what lies ahead. And here I think we've chosen this topic for a couple of key reasons. One is the value and significance of getting seeing progress in the development of better tools that will make it possible to get to zero, that will disrupt transmission, that will deal with future unknown threats that will give us better means to differentiate among Ebola, dengue, malaria, other diseases and allow us to begin dealing with sporadic incidents of new threats versus more common ones. This is just so fundamental across so many different ways to effective disease prevention and control. Second point is that there's a lot of excitement. This is a period in which we're seeing because of the urgency, because of the magnitude of the crisis Ebola posed, we're seeing a proactive approach that engages regulatory agencies, funding agencies, private sector firms, foundations in a set of accelerated collaborations that are quite important to understand and quite encouraging in that sense. There's speed, there's a sense of urgency, FDA, the Food and Drug Administration has stepped forward with guidance and streamlining of its guidance in ways that has helped move things along. We also come at this problem and we'll hear from our speakers aware of the complexity of the challenges. There are scientific barriers and uncertainties around sensitivity, around detection in the way that we need it, around the progression of disease. There's the market itself and the fact that these, the special challenges that come from unforeseen and what have been thought of as small scale outbreaks, what demand, what incentives, how to make the case for sustained private sector engagement. We're well aware of the rough operating environment, the problems of portability, functionality, reliability of transport, access to power, trained personnel and lab infrastructure. We'll hear more about that. The regulatory and safety considerations are still profound. How do you operate outside of a BSL4 lab? How do you bring about the regulatory, the flexible but safe and effective regulatory regime? So what we'll hear is a sort of realism and optimism mixed together around moving ahead. And a lot of excitement but also a lot of concern about buildings, sustainability and learning from these experiences in ways that help for the future for unknown, other unknown outbreaks, a better preparedness, a better set of regimes, a better set of approaches and partnerships that can do this. Now the way we're going to go about this morning is I've asked our three speakers to each open up with some prepared remarks. Michael Carrilla, Dr. Michael Carrilla is going to lead off and do, we've asked him to do sort of a big picture presentation on where are we. Michael is the Director of the Office of Biodefense Research Resources and Translational Research as well as Associate Director for Biodefense Product Development for the National Institute for Allergy of Allergy and Infectious Diseases, NIAID. Michael thank you so much for being with us. Rosemary Humes directly to my left will speak in the second slot and Rosemary is the Diagnostics Science Advisor for BARDA for the Biomedical Advanced Research and Development Authority at Health and Human Services. Very importantly she co-chairs the Diagnostics Interagency Group team which is the Public Health Emergency Medical Countermeasures Enterprise. Did I get that correct? Absolutely. We're off to a good start here. Here Rosemary Jean Walther will speak and offer the perspective of the Paul G. Allen Family Foundation where he is employed as an independent expert consultant in defining the role, the Ebola strategy in the role of the foundation with special emphasis on diagnostics. He comes to this job as a senior executive, lifetime executive at diagnostics and biotechnology firms in the Seattle area and as previously as Deputy Director for Diagnostics at the Bill and Melinda Gates Foundation. So we've had great fortune. We've got a very good mix of perspectives, experience, outlook here. I want to also mention we are joined today by a number of other folks. Sally Joivot, welcome from the Food and Drug Administration. Did Deborah Malick make it? We had a confirmation and Andy Weber I see is here. Andy from the Department of State, thank you so much on the Ebola team. So I hoping we'll hear from some of the other folks from the administration, from industry. We'll do these opening remarks a little bit of a round among ourselves but not too long and then we're going to come to you for your interventions and comments. So please don't be shy. So with that word, why don't we begin, Michael? Why don't you kick us off here? So let's see, do I need to do, if I just hit it, will it go to, ah, yes, okay, nope. I just went through the whole thing. I guess I went through the whole test there, how do I get back to slideshow? Hit F5. Thank you. Okay. I'll be very careful here. All right, so I'm going to have some very brief remarks to open this. I'm going to talk about some generic aspects that are relevant to diagnostics in general and then talk about how those impact, how those issues can impact Ebola and other high-containment, highly lethal pathogens and try to touch upon a number of them that can form the basis for further discussion. So I think the first thing, this is going to be tricky here. Maybe you better give me that clicker thing because it seems that... Try and enter. Try and enter. Okay. We're good. Okay. So I think an important thing for diagnostics is that, you know, typically we think about diagnostics in the frame of yes or no, and then we further define that into sensitivity and specificity. And those parameters are important from the standpoint of evaluating a diagnostic test, but while they're necessary, they're not sufficient. And presenting symptomatology as to what triggers that test to be done is, I think, very important. Relevant for Ebola is typically fever is the predominantly a major symptom that most patients are coming forward with for a presumptive diagnosis. Vomiting diarrhea may be other aspects that need to be considered, but the holy grail would be a pre-symptomatic test, but that is actually even a much more difficult thing to achieve. Now within that realm of a fever, you next have the question of a differential diagnosis. And while fever may be pathodontic or very highly indicative of Ebola, the reality is in this part of the world in West Africa, as well as in many other parts of the world, fever is a very nonspecific symptom in general, and there are a lot of other obviously endemic diseases that can be causing fever, some of which are very treatable, such as malaria, some of which are potentially severe but will have a different treatment regimen than Ebola, such as Lassa fever. So the differential of what you want that test to do will actually have a very big impact on the predictive value, both positive and negative, and a recognition of that is very important so that you make sure that your specificity panels that will define the parameters of your test take that possibility into account. Now I'm completely, what has happened here? It's doing something very strange. So my next point was time to test and time to result. And so we can develop, and we have developed quite rapid tests, PCR tests can be developed within a, the result, the test itself can be performed within a four hour time period. However, the time to get a result is actually much more problematic in that it encompasses a wide array of other aspects, that is collecting the specimen, getting the specimen from where the patient was sampled to where the laboratory is, and that will partly depend on the complexity of the test as to how portable or how easily implemented that test is in different resource settings, the need for electricity, the need for highly trained staff, you may be, or the need for specialized equipment may limit the availability of those tests. So you may have to obtain the sample and then transfer the sample a large distance. If you're talking about certain types of, for example, PCR tests, you may be batching large numbers of samples, so the test may not be able to be run on site. As soon as the specimen is received, you may have to wait, you may have to wait for the next day, you may have to wait for a different period of time. And then the result has to get back to the pertinent people who can interpret that. And so while the PCR test itself may be as quick as four hours, getting the result back from when the patient is sampled to when the result gets back may be upwards of 48 to 72 hours, and in a disease like Ebola that may be progressing quite rapidly, that time is very, very critical. Michael, I'm sorry, this seems to be going haywire, so maybe we could just ignore that and keep talking. Okay, I'm trying to think where I was up to in my... Slide two might be good just to look at that up and get a vision. Can you just put slide two up? Is there somebody if you're not going to do anything? We can do it. It won't even, it doesn't like my slide, it seems. It wants to kick off. Okay, maybe. So the next topic is disease progression. So as I mentioned earlier, we in many instances will think of a test as being a yes or no, but there are other utilities of diagnostic tests and that is to give you some degree of the severity or the temporal progression of a disease and certain types of tests may be possible. In the case of Ebola, for example, the PCR test is not only used to identify those who have the disease, but also when people have gone beyond and have actually recovered from the disease and it's used as a criteria for when those individuals may be released from the hospital. And so that's another consideration to keep in mind. There may be other utility of that, of different diagnostic tests that will have clinical relevance for the clinician. Okay, another issue that needs to be considered is when we're dealing with highly lethal pathogens, at least in the US and in other parts of the world, we define biosafety levels for how it will be handled. Diagnostic tests generally are considered sort of exempt from that until we know exactly what we're dealing with. But the ability to access those specimens, the ability to have controls that can be utilized, live viruses can place great severe limits on the ability to actually develop those tests. Because the individuals who need to have that material may be restricted either in terms of adequate biocontainment facilities or as we've done in this country with certain agents, labeled them select agents. And so that requires another level of scrutiny. Finally, in terms of that, what we have been doing and Rosemary can talk more to this specifically, is identifying those particular elements that would be very difficult for diagnostic developers to get their hands on, a wide panel of agents, while it may be possible for a developer to synthesize specific DNA in the case of a PCR test, or produce a retombinant antigen in the case of an ELISA test. The reality is that regulatory agencies would like to see how the test performs on actual authentic virus in this case. And so inactivated viruses would be very desirable in order to run through the entire diagnostic process. And so something that Rosemary will speak more about is that the US government has taken this on as a responsibility to create diagnostic panels that will contain the relevant material needed for defining specificity and sensitivity for those tests so that they can be submitted to regulatory bodies in order to provide that oversight and be able to introduce those into general usage. So I'll stop there and turn it over to Rosemary, whose slide is much more stable, yeah, there we are, yes. Thanks, Mike. And I also want to thank CESIS and Steve and Sahil for the invitation to participate today. First, I also want to introduce Barta to you for those of you who may not know Barta. Our agency sits within HHS's office of the Assistant Secretary for Preparedness and Response. And our mission space is advanced development, research development and acquisition of medical countermeasures, including vaccines, therapeutics and diagnostics for public health emergencies. So what I want to do in the next couple minutes is kind of expand on what Mike has talked about and talk more generically about the complexities of considerations for diagnostic development and for diagnostic use. I often find that people perceive diagnostics in the context of a technology problem. We just need a better widget. We just need something that's simple that anybody can use and will have solved the problem. And what I hope this slide here tries to capture is that diagnostics are really a very complex system, even in many ways, a system of systems. Many of the considerations that make a useful diagnostic relate to what we would call the concept of operations. As Mike said, why are you testing? How does this relate to the disease? And how will it impact the patient management or even community mitigation strategies? For acute infectious diseases, we're generally looking for the organism. So we need to know when is the organism present, where is it present, blood, tissue, respiratory fluids. How much of that organism would be present at different stages of disease? And that's going to vary with the course of the disease, and it's going to very much impact the clinical performance of the test. When we think about emerging diseases or rare diseases like Ebola, the kinds of research that's necessary to determine all of these things is very challenging, and animal models may not always give you the relevant information. As Dr. Krula said, right now, Ebola viruses are not detectable in blood until the symptoms appear. An experience has shown us that, in fact, we may not even be able to detect it with sensitive PCR methods until up to 72 hours after symptom onset. So the disease itself presents many challenges that need to be considered when you start to conceptualize a rapid diagnostic, a technology solution for something that would be simple to use, fieldable, and detect Ebola in the tiniest finger stick of blood. You also need to consider the operational issues, the environment, the expertise of the user, the reliability of the results in the context of the prevalence of disease in the community, and things like, are you going to be able to get the supplies to where they're needed? And when you translate all of this into the complexities of the situation in West Africa, where there's little infrastructure, there's complexities of moving things into the field, it becomes even more complex. So with all of this backdrop in mind, the Interagency Diagnostics Team, which includes Asper Barde, FDA, CDC, NIH, DOD, and DHS, developed a set of Ebola diagnostic specifications, product specifications, that included the CON-OPS. And this document is really intended to present what within the US government we feel is necessary to make a point of care test useful. Under most outbreak settings, we would say a test with low sensitivity would not be acceptable because of the risk of a false negative. But as this outbreak has grown and really spun out of control, thinking very much evolved, and there's been a greater acceptance of the idea of a test with suboptimal sensitivity, as long as there was high specificity, meaning that a positive really meant positive. And the utility of this test would be to quickly identify your hot patients, move them into isolation, into a bill of treatment units, which you could only do this if the operational conditions existed such that you could hold the person and retest in three days. And then as I mentioned, even if you accept limitations of lower sensitivity, there are other operational challenges, the extreme heat and humidity of the conditions in West Africa, the portability, the power requirements, exposure risk to the person collecting the sample and doing the test, and even a simple test will require that users receive some training. So finally, where are we? There are seven tests that have received an emergency use authorization from FDA. All of these are PCR tests or molecular diagnostic tests. Four were developed by the US government or with the US government for use in governmental settings. And three of them are commercially available and use technology that have applications for other infectious diseases. Based on a fairly comprehensive survey of the development landscape that we conducted, there are at least 37 other molecular tests and at least 20 other antigen detection tests somewhere in the development pipeline. And about half of these have governmental support, either technical assistance or funding. A WHO is collaborating with FDA and Sally may be able to speak more to that so that there's a coordinated process in approving tests even for use in West Africa. And as Mike mentioned, probably one of the biggest challenges when we talk about pathogens like Ebola is how do developers get access to the materials they need to develop their test and then to validate its performance. This has been a complex issue in the biothread arena overall. So the interagency work group came to consensus on exactly what organisms need to be included in those validation tests. We have FDA acceptance of that list. And then through funding that's being provided by NIH, the Department of Defense in the BSL4 Lab at USAM where it is developing quantified curated panels of these viruses that will be made available to developers through the NIH's BEI resources repository. And we anticipate those will be available mid to late March. So I'll close there, but hopefully I've given you some better sense of the complex issues that relate generally to diagnostics and then especially to Ebola. And I'll turn it over to Gene. Thank you. First I'd like to thank Steve and Sahil for inviting me. I grew up in the Chicago area, but in Seattle we don't get a lot of snow. Saturday I was kind of stuck inside all day for obvious reasons, but anyway, it's great to be here. I've been with the PGAF at the Paul G. Allen Family Foundation for just a couple of weeks. So I've got a few more notes that I typically like to use when I speak, but because I wanna make sure that I'm accurate in what I'm saying, but it's been an amazing ride in the short six or seven weeks that I've been working with them given the challenges that we have with Ebola and Paul's real intensity. So I'll give a little bit of perspective there, but I'm probably preaching the converter. This is a very complex problem on a number of levels. There are political issues, there are technical issues. Rosemary alluded to some of the facts. We'd love to see a pre-symptomatic, highly field deployable type test, but those don't necessarily go hand in hand. And so how we deal with all of these complexities, the logistics of how do we get even supplies into many of these countries is quite problematic and also then would apply to a diagnostic test. How do we get the infrastructure in place to be able to do these diagnostic tests? So while I know this is primarily a diagnostic discussion and a deployment discussion, I don't wanna minimize the complexities of all the other things that go into that. And I think as you'll see, some of the concerns and questions that I have is really not about just Ebola, but what is beyond Ebola and how do we think about that? So I'll try to address that a little bit as well. There are probably five key points that I would like to make or hope that we cover throughout our discussion. And one is we are still in the midst of an epidemic. It's losing some of its visibility. We're not seeing it in the headlines like we did three or four months ago, but it is still raging. And the second point is we have to be very careful about complacency. As we start to lose that visibility, we start to think it's no longer the problem that it is. And I think we've seen in the last three weeks, the first three weeks of February, where the number of new cases has continued to increase and has taken a jump up. So I think we have to be very clear that we keep our eye focused on the problem and that we don't lose sight or think that this is now a done deal. We also need to improve the near-patient diagnostic. I think as both Rosemary and Michael had said, many of these tests, if you have to send them to a central laboratory in order to be performed, it's taking 48, 72, I've heard even as long as five days to be able to get results back to the patient. Given the rate of deterioration of these patients, that's quite serious. I think the other thing that many of you probably know about is we have these, I don't wanna call them detention centers, but basically where people are waiting to see if in fact they have Ebola. There's 20 plus diseases that present themselves with similar symptoms as Ebola. And we put many of these people that are not sick with Ebola right next to patients in beds that are sick with Ebola. And those of you that have been in this space know what DOT stands for in TB, right? It's directly observed therapy. Well, now we have directly observed transmission because we're putting these people right next to each other that don't necessarily need to be there. So being able to get that accurate diagnosis quickly and not putting these people at risk is I think a very serious thing that we need to be thinking about. The other key thing is that while there's been a lot of focus about Ebola, there have been so many cases and I was gonna try to look at the statistics. Somebody once told me that in the last 21 years we've had 19 outbreaks and I think if we look at the last 38 years there have been like 27 outbreaks or something like that. So even once we get this controlled and contained it's not a matter of if there's going to be another outbreak, it's really a matter of when. And so how do we put the surveillance tools in place and do we have the political will to be able to maybe spend a little bit more on every test basis, but to be able to detect Ebola the next time we have this outbreak and be able to hopefully mobilize more quickly and contain the outbreak better than we have in our current situation or the current crisis? And I think there's another aspect and a number of people that I've talked to in trying to do kind of my homework and research here is we really don't understand the biology of Ebola very well. We really don't know a number of things that really will help frame what does that target product profile need to look like? How do we actually define the use cases and potentially different products that we need in different use cases to be able to address the Ebola outbreak? So one of the questions that, as he'll ask me to address is why the Paul Allen Foundation in Ebola? What was the connection there and what was the interest? Well, as I understand it, Paul and his family have really had maybe an infatuation as strong, but they've really loved a lot of things about Africa and he has many other investments in Africa in terms of the environment, looking at animal conservation. He's got a major investment in grant looking at elephants and elephant movements and things like that. So there's always been this very strong connection to Africa, but also kind of this link between the human and animal health. In 2009, he made two investments in some specific research projects involving Ebola in primates. I have my graduate degree from the University of Washington, but unfortunately, he's also invested in the Global Animal Health Department at Washington State University, so there's no competition there, but he's clearly very, very interested in animal health and those sorts of things and activities that happen in Africa. So when these reports started to come out in public domain about the outbreak in Ebola, he took very interest and had the staff at the Allen Foundation start to look at where they could make investments, and in July, they made a couple of grants to actually look at getting supplies into the area, into Western Africa, and then in October, he made a commitment of at least $100 million to fight the Ebola epidemic, and so part of the challenge, frankly, was this was passionate, this was something that Paul cared immensely about, but they really didn't have the infrastructure to be able to do that, and so in that short timeframe, they've actually been able to mobilize a number of folks, bring in a number of consultants, such as myself, and in the last several months, they made over 20 grants in this space. Two of those happened to be in the diagnostic space. The four operational principles that we were asked to abide by was one, to fill gaps, so we didn't wanna be redundant, we didn't wanna do things that others might be doing, which is easier said than done, because there were so many things happening without a lot of coordination, to build partnerships with others so that we could leverage our funding with other funding, and also be quick and be nimble. So, you know, having come out of another foundation where getting grants out the door took quite a while, I can say that the other foundation across town is very, very quick at getting their money out the door, and probably close to two-thirds of that $100 million has already been expended in providing supplies and building some infrastructure in the three Western African countries. Couple of areas, and I think in the interest of time, I won't go into as much detail, but there were two major areas sort of in the diagnostic space that investments have been made. We did two co-funded grants with the Gates Foundation, one for Chorgenics and one for Cepheid, so developing a lateral flow rapid test, which received WHO EQAL approval last Thursday, and I understand that the FDA approval will be coming hopefully very soon as well for the EUA, I shouldn't say approval, Clarence, I think is what we're calling it, or authorization, authorization, sorry Sally. So they've received the authorization from WHO, and hopefully from the FDA fairly soon. The other thing that not surprisingly that Paul's very passionate about is data, making sure that we have evidence-based decision-making much as his co-founder Mr. Gates. So one of the big issues was trying to get accurate, timely information about new cases and about Ebola, and so finding that in many of these Western African countries, it was very difficult. Internet systems weren't there, Wi-Fi systems weren't in place, and so some of the investments that he's made have gone to trying to build up that infrastructure, even if it's on a temporary basis, but to be able to bring in some of that infrastructure so that you have coverage, and as we get data, we're able to report that in real time, to be able to monitor some of these micro outbreaks that we see, so we think we're getting something under control here, it's kind of like squeezing the greased watermelon, all of a sudden something pops up over here, and I think as we alluded before, one of the things that's most frustrating and most concerning is that that availability of epidemiological data is not very good, and so we're finding that in some countries, Liberia, we're getting close to 100% of our contact tracing is where the new cases are popping up, and at the other end, we're getting 20%. So knowing where and being able to do better contact tracing so that we can follow the epidemiology and be able to track these things and hopefully intervene more quickly is gonna be very important, and that's a combination of having good, near patient diagnostic tests, as well as the ability to get that information and be able to manage that information in a real time basis. I think the other things, we know a lot about what's happening, if you will, in terms of the cases, we know that there's 23,253 cases as of last Wednesday, and I think the number of deaths is getting close to 9,300, so it's still continued to be a problem. As I said, we've seen new cases increase. I think we've had 124, and then I think two weeks ago it was 144 new cases, so we're still seeing increases in the cases, and we need to make sure that we keep our eye focused. But I think there's also a number of issues that we need to get answers to, and so as my recommendation, we'll be going back to Paul about where our funds and what we can potentially do, it may be around a better understanding, truly, of the history, if you will, the natural history of Ebola, so that we can move forward. So, for example, here's a series of questions. Some of you may already have them. I'm not sure any of us will have the answers, but to what extent do asymptomatic infections occur? How do the viral load levels compare in the different specimens? So we talk about blood, but we say that Ebola could be transmitted through body fluids. So what is the level of viral load in saliva or urine or fecal material relative to blood? If blood is the index standard, is saliva half that? Is it a quarter of that? Is it twice that? We don't really know some of these viral load things, so as we think about the type of specimens we'd like to use for the diagnostic, it's important to know that kind of a question. When does an infected individual become contagious? Rosemary mentioned that it may be 72 hours post-symptoms before we can do the detection. Are they infectious immediately before symptoms, a week before symptoms, the onset of symptoms? We don't really know when that trigger occurs, and if we really want to stop the spread, we need to be able to know when we have to be able to detect it to avoid that spread. The other question that I've been struggling with is, how does the host immune system affect the doubling rate? When we think about the immune status, we think about diet, we think about all sorts of things, what kind of initial dose did somebody get, how does that work into it? Modes of transmission, there was an article last Thursday many of you may have seen here in the Washington Post that suggested maybe it could be airborne, may not be as prolific certainly as influenza, but maybe within say a four-foot area there may be some exposure. So we need to not say okay it's not airborne at all, we may need to do some more research and understand is it possibly airborne and if so what do we have to do there? Do co-infections with other febrile illnesses impact the mortality rates? And if we're only testing for Ebola, we're not testing on some of the other febrile illnesses, how do we understand that dynamic? Can we identify a unique host response? So rather than looking for the pathogen itself, is there, and I've talked to a number of academic groups that are looking at host responses to see if we might be able to find some sort of a unique immune signature that would give us some indication maybe earlier than actually the onset of symptoms or having a sufficient hyrremia to be able to detect the disease. And do we really understand the animal vector? We think it's bat-born, but is it any other animal vector and is there some way for us from a surveillance standpoint to be monitoring the zoonostic aspect as opposed to just the host? So anyway, I'm sure that you guys all had those questions and a myriad of others, but I think that those are all critically important and I think that the WHO has done a nice job of defining a target product profile and I won't go into those details. I think you've probably all seen that or have access to that, but I think the key takeaway is that none of the tests that we've seen thus far, whether it's the seven that had EUA approval or even the 18 that I think were at the WHO, none of those really aligned closely with the WHO target product profile recommendations. And so what do we have to do and where do we need to go to actually fulfill that? So I'll stop there. Thank you. Thank you all. So what I take away from your presentations is we're still at an early point, right? We're still at a moment where it's very hard to predict where we're gonna be in a year's time. Is that correct? Would you agree with that? I mean, there's a lot at play. You've got a lot in the pipeline. Most of it is PCR based. Some of it is antigen. Maybe you could say a few words around those two broad categories of tools and what does that mean and why are we seeing a proliferation outside the US-20 antigen detection tests and we're putting most of our emphasis upon the PCRs. So I would say that we're not necessarily putting an emphasis on one over the other. PCR has been the standard for the outbreaks that have occurred and largely those were smaller outbreaks and so the best test I think was the standard. As we've looked at antigen detection tests and there are a number of companies and the US government is supporting a number of those efforts along with other foundations. It's what can you accept that won't first do no harm and so an antigen detection test that we know based on current technology is gonna be at least two logs less sensitive than PCR. There are significant implications for that and as I tried to say the technology itself is not the only solution. We don't know a lot about what's the concentration of virus on day one of symptoms, a day zero of symptoms, day 10 of symptoms other than we know the concentration rises. And I think I've been embedded down at CDC for much of the response and there's been a lot of discussion around the questions that Gene and Mike and I have raised but when you're in the immediacy of a response and urgent response, the critical thing is to do what you can to control the outbreak and studies that would normally be very much part of any outbreak have really had to take a back burner because the response and controlling the outbreak has been job one. So now I think many of the government partners, academic partners and developers are saying, okay, how can we use what we have learned or could learn from this outbreak? The other issues, some of them are political. You can't just go in and start doing research on people in these countries. You need all kinds of agreements with the countries and just for some parts of the government to get agreements to be able to move specimens out of the country or move data out of the country so that evaluations could be done was a real challenge and took months and months and months of negotiation. So I don't think that we are particularly focused on one over the other. Both have application and I think as the outbreak winds down, the better test is again gonna become more important because with malaria co-circulating, other diseases co-circulating, you're gonna really wanna be able to provide the best diagnostic. If we had had a point of care test back in August, September, October that was reliable, yeah, I think it would have made a huge difference. But as we were talking in the green room, the other issue is marketability and sustainability. This outbreak is getting better, thank goodness. What's gonna be the role of an Ebola diagnostic test six or nine months from now? Who's gonna wanna manufacture it, sustain it, stockpile it and these are real budgetary questions that would have to be addressed. What comment I would make about PCR, why there's a sort of migration and first of all, it's relatively easy to bring a PCR test online from the standpoint of sequence data is generally available so that is something someone can actually do on their own without any involvement to begin with in terms of the development of the test. The other utility of PCR is that it not only provides the yes or no is this person infected but it also provides a degree of disease progression by looking at seats, quantitative PCR allows you to look at CT values of how severe what the viral load is. It also provides a sense of when the patient is recovering when you could say yes, we can't detect virus anymore in you. And so it has those advantages. I think the antigen tests, while they can be done independently in terms of taking sequence data and expressing antigen, what has largely been a approach people have taken is to identify researchers who have been working with either patient specimens or other access to BSO4 facilities and develop monoclonal antibodies specific for those antigens that have demonstrated some performance either on authentic virus. And those are a little harder to come by. There's obviously intellectual property tied up in that so it involves a little more of a negotiation back and forth to bring that on board. I think as Rosemary has highlighted the sensitivity of the antigen test remains to be really demonstrated relative to PCR. We just simply don't know whether it can provide a particular tissue source for the virus as to whether we can see earlier positivity relative to PCR or equivalent sensitivity to PCR. And I might just add a couple of other points. I think that lateral flow tests are often perceived to be very easy to run. But they're not necessarily that easy to produce and or that easy to run. Case in point, if you think about the avidity and affinity of the antibody or antigen that you're putting down, that will drive the quality of the result that you get. And so to the point about having a high specificity, if your antibody that you're putting down isn't that good, you may get very poor specificity, you may get very poor sensitivity. Conversely, if you have very good antibodies that you're putting down, you can improve that. And so what we don't know I think yet is how these different lateral flow type tests or rapid RDT type tests might perform one versus another because we don't know yet really the quality of the antibodies that they're putting down. I think the second thing is and some data that we had done at the Gates Foundation around lateral flow tests is compliance with procedure. While it seems to be very easy, I had two drops or I had four drops and I wait three minutes and then I had two more drops. Some studies that we did in Africa indicated that compliance with procedure was as poor as 4% in certain instances. So the test was supposed to take 15 to 20 minutes. The average time that a healthcare worker was with an HIV patient was eight. So they were giving a result before the result was really complete. And so the point being is we need to think about lateral flows in not just a very simplistic strip paper type test. Also the reporter mechanism that you use. You can improve the sensitivity and the performance of those but they may not be visible to the eye. You may have to have a handheld device to be able to do that. That may not be a bad thing because you could have the connectivity to then also look at where do you have these outbreaks and how can you track where you've got new cases and so on. So there are a lot of things that I think we need to think about even on the simplistic if you will lateral flow type tests. On the PCR type tests I try to stay away from PCR although I know it's become the Kleenex of amplification but to think of it as amplification tests because there are also isothermal amplification tests that could be field deployable. Most of the PCR tests while they become faster you can usually get them completed in less than an hour. They typically because of the thermal cycling and all the other sorts of things are not as able to go out into the field. But some of the isothermal technologies that aren't as power hungry could actually go out and be done and some of them frankly can be done in 15 to 20 minutes the same length of time that it takes to do a lateral flow. So I think that there are opportunities. Part of the challenges that I think we faced here was we talked about short term and we had this discussion actually at the Allen Foundation is what do we mean by short term? We mean now being able to get a test and the technology that we understand and has developed that we can get into the field and we can start to test for Ebola today. Anything else is really more of a midterm and a longer term that could be a solution and it may again to the business side we may need to think about surveillance where we could have multiplexing where now Ebola becomes one of three or four or five tests that you're actually looking for so that you've now got sentinel tests being performed. Malaria for example, you could do a malaria, a dengue, a yellow fever, a typhus and an Ebola. Maybe you've got four or five multiplex and now you're actually able to monitor and see if you do have an outbreak at some point. This is where my comment before about the political will because it's gonna cost more to be able to do that. The question is, is it worth that cost to be able to avoid a significant outbreak in the future? Thank you, I would like to. Sahil, I'd like to ask two of the senior administration folks who are working at these issues from their own perspective. Andy Weber from the Department of State, from the Ebola Deputy Director of the Ebola Task Team under the Secretary of State. Andy, could you put this in context, what we're talking about in terms of US foreign policy priorities here vis-a-vis Ebola? And then I'd like to ask Sally to comment a bit on the FDA experience if you don't mind. Well, the President Obama recently hosted a group of the Ebola responders but also the philanthropic organizations and some CEOs from the tech sector to talk about. First of all, we've achieved a lot in bending the curve but to get to zero, we've got a lot more to do and these tools are lacking and it's been over a year and we need these tools fielded. So I'm very interested in accelerating. So I just, I wanna ask a question to the panel since we have both sides represented here and I'm gonna be speaking on Ebola response at the Silicon Valley Community Foundation on Wednesday. What should I be asking from the US government side? This is for Michael and Rosemary from the philanthropic and tech sector to help us with this key problem set and then I wanna hear from Jean, what are the frustrations and over the last year of trying to help the UN organizations, the US government from the philanthropic sector because I think we can do better in accepting help with all this goodwill. Thank you. Thank you. Would you like to respond and we'll come over to Sally. So I think if you're asking what are you asking me what I would like to see the private sector in terms of, I think the biggest, so as Rosemary has remarked on, there's actually quite a bit of activity going on in the private sector. We're actually very impressed with that level. I think the one issue that we tend to find quite frequently is that there tends to be more of a specific focus and as was mentioned, the ability to do a multiplexed assay that would have real clinical utility is more complicated, more difficult, but is much more highly desirable to be able to develop. And so having a test, the test for a specific entity, if you just had an Ebola Zaire test that would not detect Sudan or Ivory Coast or Tifar or through these other ones would not be useful. It may be very close to being developed and fieldable, but in the long run it doesn't have the clinical applicability that we would like to see. So there needs to be, I think the biggest issue with diagnostics that we see is that the ability of technology to respond to a specific type of diagnostic dilemma doesn't always align itself with the commercialization potential of that technology and the clinical utility of that. And sometimes those are different groups that need to be brought together. I recognize that it's very difficult for diagnostics companies, particularly small players, who are struggling to get a particular technology and don't wanna overwhelm themselves, but to really make a test that we could really get behind and move forward, it would have broad-based utility for a lot of outbreaks in this sense. I think that's the real message to see. They need to be a little bit more bigger picture instead of just a test for a specific infectious agent. Russ Mayn? And to Mike's point here in the US, we've talked about both from a bio-threat preparedness perspective, the need for something that is more multiplexed, but also the everyday returning febrile traveler. And I think that's a market niche that needs to be explored. We have many more people returning with unknown febrile illnesses. We've had a patient with Marburg in the United States who went in 10 or 12 days with unrecognized infection. Actually diagnosed herself. Because a friend of hers was then diagnosed in another country. We've seen LASA in Minnesota. So I think there is a market case to be made for some of these tests. And I think the other is that there needs to be consideration to, as I say all the time, of it beyond a technology and that developers need to think about the infrastructure that's gonna be required to support these tests. Jean talked about HIV testing. Even in the United States, we've seen issues where rapid tests, rapid flu tests, rapid strep tests, rapid HIV tests are not used properly. And so putting them out there and making them available is only one part of the solution. And companies have a responsibility, in my opinion, to make sure that there's training and technical support to the people who are using the tests. You know, I might just piggyback for a second because I spent a long time in the private sector. So, you know, the market dynamic aspects as well. At last count, there were over 70 groups working on developing Ebola diagnostic. I don't know of a single diagnostic area where you have enough room for that many players in the space. And when you have a disease that's hopefully of short duration or relatively short duration, there's not gonna be enough room, if you will, or space for that many players. So, I think being able to identify which are the best technologies or the best products or the best companies that can execute on some of these things and then making sure that we give them the right tools, the right support to be able to play in the space because otherwise I don't think there is that kind of an opportunity. We mentioned it before and I think back to some of the influenza stockpiling that was done for the vaccines years ago. Do we need to think about that relative to Ebola diagnostics? Do we need to have certain stockpiles in various places so that one, the companies can at least forecast and say, I know I'm going to have X number of tests that I'm going to be able to produce on an annual basis to keep in stockpiles such that when there is an outbreak, I can have an immediate response. So, I think that's something that we, you know, when between the government, let's say, and industry, having some way of sort of an advanced market commitment, as we called it, that we could stockpile and have those available. Can we identify certain instrument platforms such that, for example, if you had a handheld device that you were going to run these tests on, maybe you had 50 or 150 of these that are stockpiled and as soon as you have that outbreak, boom, you're able to get those out into the field and so on. So, I think that's a way of how can we make a market that's attractive to at least a few players? I think, to your other question, Andy, I think it's from the funder's standpoint, it's, the frustration, I think, has been the lack of coordination and so as funders are putting a lot of money and governments are putting a lot of money into trying to fight this and do this, how efficiently are we doing that? How, you know, how much redundancy or repetitiveness or gaps are there because no one's really helping to coordinate and identify those things and so in many ways, yes, $100 million is a lot of money to throw at this but in the total cost of what's being spent, it's not and so how do we make sure that the money that is being committed is being used in the maximum effectiveness and efficiency and who is that, has that responsibility to do that? Is it the US government, is it the African government, so who and where do we do that and that I think is something that we need to think about whether it's for Ebola or the next outbreak or the next pandemic. But if you were to suggest concrete steps to improve the coordination, what would you suggest? Well, take it from the USG side, I mean, just on the USG side, what would be? Well, yeah, it's a slippery slope, Steve, but I think that frankly it's a large part of what the World Health Organization is charged to do. I mean, I think a big part of their remit is when you've got a World Health crisis to coordinate that and the US government provides a lot of money to WHO, the Gates Foundation provides a lot of money to WHO, I think being able to have a group that we can go to and say this is your remit, this is your responsibility and make sure that they've got the right tools to be able to respond when that happens. Well, you just had this special session, January 25th, right, of the Executive Board of WHO, you had a fairly elaborate reform agenda put through and a number of benchmarks set between now and the World Health Assembly, and so we shall see to what degree those benchmarks are successfully achieved, but in this area is it felt that WHO has been particularly weak in this area or my sense has been that on the scientific and convening side of things, that the performance was reasonably okay at different points, is that not true? I'm not sure that I've seen that coordination certainly in specifically the diagnostics, for example, has occurred. Okay, Mike? I mean, the one comment I would make is that I think that unfortunately it's very hard for anyone to make the case for something that's a very unusual rare event that we should be doing something more than what we're doing already about it because there are so many other issues and prior to this West Africa outbreak, the average number of Ebola patients since the virus had been identified was the average was about 40 patients a year. It's very hard to see why there should have been a huge mobilization effort and although you could say well, we could have predicted this would have happened, and there's a lot of things. Unfortunately, as a race, we tend to have humanity, tends to have the notion that until it happens, we don't think it's possible to happen. So the West African outbreak I think has shown us the potential at what Ebola can do and now you're seeing a very large concerted effort to try to address not only this outbreak but to really put long-term activities in place that will go a long way into preventing a future outbreak of this magnitude and actually be able to address other future outbreaks in a much more comprehensive manner. Rosemary, you had something you wanted to add. Just to the point about specifically addressing diagnostics and what the US government canon has been doing and to Jean's point about many, many, many companies have entered this realm. So through the interagency group, we tried to build on what WHO's target product profile had done and create a set of product specifications, including the operational expectations for those tests. So that as companies, and I can tell you, companies were coming out of the woodwork to Bardo with the next best, greatest and latest test that could detect asymptomatic infection. They were absolutely sure of, but they had no idea what asymptomatic infection looked like or what you would actually measure. Presence of the virus. We don't know what would in negative mean. This is one of the big questions we talk about with asymptomatic, but I can, we would have loved to have been more nimble with creating these product specs, but the absence of a lot of natural history data, a lot of understanding about the disease and what presents when, the debates around what was the minimal limit of detection that we could accept. What was the lowest sensitivity that we could accept? How would you even measure that? Viruses are complex. Do you measure them in terms of live virus infectivity? Do you measure it in terms of virus particles? Do you measure it in terms of antigen particles? I mean, there's a lot of complex detail to this that the scientific group really spent a lot of time debating. And so I think one of the things the US government can do is try to look at these things, identify as Jean has helped with what are the gaps in knowledge that we need to fill so that we can have better vaccines, therapeutics and diagnostics. But the next Ebola outbreak may not be Ebola's IEAR. It may be the Sudan and what is gonna be different about Sudan than Zaire and will be, will we have all the right tools in place for a different Ebola virus? Sally Hovant from Food and Drug Administration. Would you care to offer some reflections on this period where you've obviously been quite busy? Thank you for joining us. Very busy. Let me give you a little background. For the last five or six years, we've actually been working interagency very much in this sphere, working with DOD, with Andes, a group working with NIH, CDC, BARDA. And we had some tools. We had the tools that we used for the H1N1 outbreak. We learned a lot of lessons from that. What could we do to help people? First of all, the emergency use authorization is something that was put together as a result of 9-11, getting things through much easier. What are we asking for? We're asking for minimum validation data, mostly analytical data. And in fact, for these molecular tests that we had, we were looking for the kinds of data that anybody who's developing an assay must be doing to be able to say that their assay will go out there and work. For the antigen assays, we have felt that maybe, because of all of the different circumstances, we would like to see some data from West Africa. And that hasn't been easy for people to get, so we have a plan B and we have a plan C. We basically had that for every biothreat agent. When we talk about specimens, what's the best specimen that we'd love people to be able to test their assay with? It's a fresh specimen out in the field. For these biothreat organisms, ribola, not possible in many cases. So what's the next best? A good retrospective bank sample as long as you can show that that sample is equivalent to a fresh specimen. What's the next best? Spiking material into negative serum or plasma or whatever the specimen is. And for H5, we had to go down to something that sort of simulated it because of the lack of specimens. You've heard all of the different barriers that are there for a manufacturer. And what we've tried to do at FDA is scientifically work with everybody and say, what's the least burden something we can ask for a developer to get something out the door as quick as we can. The other program that we had was something called a pre-emergence use authorization. And I have to say the DOD picked this up and we've been working with them for about four years now. We have 75 pre-EUA submissions on all of the biothreat organisms. That they're working on. And they gradually send this data into us. Basically, the idea is if there is an emergency, and in this case, the DOD were right there, we had looked at their pre-EUA for the Ebola viruses immediately that the emergency was declared in August. We turned that around and authorized that easy one assay. That's the assay that's in the public health labs at the moment. That's the regular assay. But here's a tool that we used to be prepared and DOD have a list of other assays, including the Ebola, other Ebola assays that would be ready to go. But of course, that's just a restricted amount of, what happens if they should come here? We needed to be able to get commercial companies who have the capacity to manufacture a large scale and be able to take, like they did for the pandemic H1N1, when the public health labs were overwhelmed by the number of specimens that were being sent in. So we try to encourage the commercial companies. One of the things we had this time was a large commercial company. In fact, the largest diagnostic company here in the US, making an EUA application. And we authorized that assay for Roche just before Christmas. So here's a company that's not going to make probably money out of that, but actually came up to the bar and made it. That was the first time that we've actually had one of the big companies. So we considered that to be a plus. Easy to get the molecular assays out. As you've noticed, there's been seven of them that we've been able to get through. Antigen assays. Difficult, you've heard the issues. We've been working with several companies, hand-holding them through, and actually you already said it, Chorgenics probably out tomorrow with an authorization. So we'll get that out the door. But it's been difficult. We've had to hand-hold that small company and help them every step of the way. But we did work with WHO. That was the first two. In fact, some of the data that you'll see in the package insert for Chorgenics is the data that was generated by the WHO team in Sierra Leone. Very good data on fresh whole blood finger stick. So that's a plus two. We will work where we get the same information in from the same company with WHO. We have that memorandum of understanding to work with them as long as the company is okay with that. So we felt that that was needed, that harmonization. You couldn't have WHO going out with X and us say you can't go out with that. So we've been working with that. It's not an easy task, but we've been able to do that with multiple phone calls and meetings in Geneva. So those are some of the things that we've been doing. We have several other antigen tests in the pot. What we did was also prepare a template. So basically we gave companies, anybody who was interested, we would send them templates. In other words, fill in these areas. And basically that becomes the EUA, but we do interactive review from the very beginning. Send it in, tell us what your assay looks like, tell us what your probes are, tell us what your antibodies are, and we'll be working with you as you get to the point of generating the data. So they go out there knowing the studies that we've asked for, we work with them, and they're able to, by the time we finish, we say, okay, send it in. There you go, there's your emergency use authorization. And that's what Coregenics did this weekend. So what we've seen all the data, everything is ready to go. So we're trying to make at least burdensome from the point of view of the regulatory side. But we do have to all make sure that what goes out the door works. So being at FDA is interesting. You're damned if you do and you're damned if you don't. But we've tried very hard to get these out as quick as we can. Sally, I just ask you, since you were saying that you expect FDA in the next day or so to issue an authorization on the Coregenics antigen test that WHO approved or authorized at the end of last week. Does this now mean that this 15 minute block test that it will be disseminated fairly rapidly for use? What does, what happens next? Well, according to the company, they are able to produce a large number of tests. And again, that's one of the criteria, even though it's not the only criteria is, is this smaller company or is this medium sized company able to deliver? There's no point in, we can't actually refuse somebody on that basis. But if we're trying to prioritize, I'll tell you, we'll go for the one that can get more out there than the one who has maybe two instruments placed already. So the expectation is that this will be deployable in West Africa, very rapid. They have roughly 50 to 60,000 tests and that's what they told us. And they can produce 10 to 15,000 I think per week. And if they need more, they can scale up from there. So that's my understanding from the company. Okay. And how would those be, what's the dissemination method for something? You get a test that's approved, a new test. It's not the end all and be all. I mean, we know there are limits to its utility, but it's still, and it's an additional new tool. So how will that be, how will the navigation happen in terms of getting it into the right places? My understanding is that they've been in contact with many of the providers. So they're working with partners in health, they're working with MSF, they're working with others that are actually involved. So they would be actually purchasing the product and getting it then through using their system into the field into actual use. Yeah. Michael, did you have anything? No, I was just gonna say that this is an issue that is completely independent of the capabilities of the test itself, but exactly how it will be deployed, how it will be utilized and how the clinical utility will actually be assessed in terms of the actual outbreak utilization, I think is an important question that is completely independent of the regulatory aspects of whether or not the test is suitable to go forward. Although, interestingly enough, from the WHO trial, they did come back with some safety issues that the company will put into place. So actually having them go out and do that trial did give everybody a feeling of what needs to be looked at very carefully. You know, there was this, do you have a cap on the Liophilized standard that's metal that could pierce the glove? Many things that are associated with the risks involved with people going out there and doing testing potentially in the field. So I thought that was another aspect that we've never had to really deal with before. Right, my understanding is that this test has probably had more actual testing with real samples than many of the others. The others have used inactivated and other sorts of things. Yeah, and it's getting more difficult now as the number of positives go down, the same for the vaccine trials to do that kind of field testing. Let's go to our audience and seek some brief comments or questions. And you can of course direct those to Andy or Sally as well if I may speak for them. And what we'll do is please be very succinct, identify yourself, be very succinct and we'll bundle together for at a time. So sir, right here. Good morning, my name is Alpha Diallo. I'm the laboratory director of our DC Public Health. Public Health Laboratory in Washington, DC. I have a few comments and then maybe just a plea. My first comment is... Please be very succinct. Right. One comment or question please, each of you. So we've got a lot of people who want to jump in. I do need to make the comment before I make my plea. And my comment is I want to... I would like to see a lot more operational approach, a discussion on this, on the development or availability of a test for Ebola. The one case that has been mentioned or what has been said so far is that there is a lack of infrastructure in West Africa or for that matter, anyplace else. That should be a key point, lack of infrastructure, but also not, I want to make on that point the plea to have a research and development component built in to the countries that are affected by Ebola or by any other outbreak in the future. I don't know if it makes any sense. That's great. Thank you. Over here. Thank you and Craig Smith kind of doing what Gene did in the less nimble NGO in Seattle as a consultant in surveillance at the Gates Foundation. Seeing Gene's surface is wonderful. We need more individuals with integrative capacity in the space. The comment that I want to make in the question to Gene is could you elaborate more on the host response? We have focused on pathogen and forgot the reason why people die from these illnesses. And I think the matrix should absolutely include that. And unfortunately in the silos of how we actually look at proposals, we haven't acknowledged the importance of the host response. Hold on just one second. Let's take two more here. A pocket area from the University of Toronto. To what extent does this global effort involve the companies that make the diagnostic machines? Either the hardware and the software to come up with things that are scale up that are small, portable, able to be used without a lot of training, safe for the user and the patient? And is that something that needs to be looked at not only for Ebola but for other diseases that happen in unusual isolated places for which you need a rapid diagnostic? But the machinery surely and the software in it must surely be part of that. Thank you. Yes, over here, yes sir. Hello, George Christopher from Medical Account Measure Systems within the DOD. One of our strategies is to develop assays that can be run on commercially available FDA-cleared devices that are used every day in clinical practice for the identification of common pathogens. So this may address some of the points raised today about operator proficiency, sustainability and cost of goods. Thank you. Who wants to jump in? So I'll make two comments. One about host response, absolutely key. And Barda is supporting some work to look at Ebola response. But the animal models don't always translate. And again, as I said earlier, in an outbreak of this scale, trying to collect specimens and do those kinds of studies would have been very challenging. A lot of specimens now have been brought back and that may be possible. The other is that host response to infectious diseases may be very non-specific in a lot of ways. One of the, and what is characterized for one outbreak may not necessarily relate to the other. And the example here I will use is that this particular outbreak has been much more color-alike than a typical hemorrhagic fever. So if we looked at host response for a hemorrhagic event, would that absolutely correlate to this particular outbreak hard to say? So Mike and I have had this conversation. I think host response is the holy grail. But when you talk about these rare diseases, how do you get that kind of information? We don't have a lot of people lining up volunteering to be infected. Although I have a list. The other point about companies and the DOD remarks, we at Bard have very much looked for companies that have an approach that their technology would be useful for routine everyday diseases. So that the equipment has been standardized, the safety issues have been addressed, and the people who use these tests know what they're doing every day. So then it's much easier to put a novel detection assay onto that. And so I think that's something that we at Bard have very much support. The only other aspect I would add to the host defense aspect is I think it's very important. It is the holy grail. We think that long-term if we have sufficient clinical information, and that's been the biggest glaring lack in terms of hemorrhagic fevers in general, but Ebola specifically in terms of what exactly is going on in humans. I think there is the parallel aspect that it's not simply identification of host defense to identify an Ebola infection, but it's also appropriate management of the organ dysfunction that that disease causes. Now that is a whole separate issue that does need to be addressed, but it's a very different picture because we know for example in these patients hypokalemia can be very severe, but can be very easily treated, but that requires a blood sample. And when you're dealing with an Ebola infected patient where you have the caretakers gowned up in such a way, it's very difficult to be drawn blood on a routine basis. So you're not talking about any particular technology that we don't already have. You're talking about being able to use particular types of technologies that most physicians would feel this is just part of general medical care, but using it under conditions that are very difficult to address and at the same time that the response may be another needle stick into the patient in terms of IV fluids, electrolyte replacement, those sorts of things. So there's a whole patient management issue that having the particular diagnostics to recognize that to actually implement clinical care based on that is a whole separate issue. And again, this is the first outbreak in which we've had a lot of experience in terms of struggling with these issues. Jane? I'll try to answer Craig's question. I think we've gotten a bit of it here. I mean, it is a very difficult question to answer from the standpoint of the immune response or human response may not be very specific, right? And so that's why I mentioned a unique signature for Ebola. And so how could we get there? Not to say that it doesn't exist, but what would we have to do to get there? We don't necessarily have the samples because you would need to look at contact tracing and be able to monitor these people throughout the course and in Sierra Leone where it's only 20% that are actually, the new cases were part of the contact tracing versus Liberia where we could actually get 100%. So we maybe have a better luck if we could get these serial bleeds from these people and then be able to monitor to see or to analyze them to see is there something unique that ultimately an Ebola patient has at some point earlier? What's the size of that? How many samples will we need to be able to find that kind of signature? So, and many people, many people much smarter than I on our immune response and human response have indicated that don't even waste your time. There's no way that we're gonna find something. But to me, it is the Holy Grail and it may be worth doing and back to the understanding the natural history of Ebola. It may be worth that kind of a study. High risk but potentially high reward. So difficult not saying we could ever find it but I think it's worth the investment to try to make that happen would be my recommendation. I think the other two questions, the last two questions were somewhat related in a sense in terms of the equipment and having standard equipment and that's why I was saying earlier about a pandemic response being able to have stockpiled maybe additional instruments that are routinely available that you can then quickly add another test to. Because again, I think that improves the business model, right? If you've got a handheld device that's already being used to monitor influenza, for example, being able to have something. And the other thing, frankly, as I mentioned, the device that could also report, communicate the information. If you're doing a multiplex, heaven forbid, I would wanna have a human eye trying to read five or six or nine different lines and making sure that we know which line was really the test that was positive. So, again, having a routinely available, standard available instrument to be able to do that, I think would be vitally important. And I think to your question about operational questions and laboratory infrastructure, that is something that the Allen Foundation is quite interested in. Whether it has to do with the training of the healthcare worker, the peace of mind of the healthcare worker. So one of the investments that we've done here in Ebola is with Medevac. And so if a healthcare worker comes down ill and needs to be Medevac out to be treated, those costs are being covered by the Allen Foundation or those costs that are unmet by others are being supplemented by the Allen Foundation. So we wanna make sure that there's a combination of training the people to be able to do the care, as well as the diagnostic tests, but also giving them some security that if heaven forbid something happens that they will be taken care of. And that's not something that's gonna fall on them. We're getting near to the end of our time for this morning. Dan, did you wanna offer any comments? Having practiced in both Liberia and Sierra Leone. Do we have a microphone? Thanks, Steve. My name's Dan Lucie from Georgetown University and I had the honor to be able to work last August and Sierra Leone in October, November at MSF Hospital in Monrovia. And I'm going back next week to Monrovia. So really appreciate all the comments that have been made by the panelists, as well as by Sally and by Andy. And for me, what Gene said about now, the near future now, it's now, it was yesterday. It's still going on, the outbreak, the epidemic. And I'm not confident that we'll get to zero human cases in the regional outbreak. And again, the virus is always gonna come back from the animals. That's why there's been 25 outbreaks in 76. So I think it should be strong momentum going forward. I think this is different than all the other outbreaks as I think everyone, including Mike said, and I think everyone believes. I guess the one thing from the clinical point of view, so I'm gonna actually use physician and clinician and I've never experienced anything like taking care of patients with Ebola, both from the extremely positive part and the negative part. So extremely positive. I've never done anything as a clinician, been part of anything that as meaningful as caring for patients with Ebola. We had many, many, many patients in Monrovia and a fantastic team of nurses and nurses aides and physician assistants from Liberia. But there were just three physicians taking care of 135 patients. So I had 46 patients the first day on October 3rd and you're only supposed to go in for 45 minutes in the morning, 45 minutes in the afternoon in your heavy protective PPE, which I totally believed in and I felt totally safe with and I had physical contact with every patient that I could as long as I could every day, every morning, every afternoon. It's the one thing I, to be brief, with regard to Mike's comment and the issues about host defense, so between October 8th and November 13th are four tents that I was part of the Liberian team caring care of. We had 74 survivors, 70 survivors and then four more that admitted who survived afterwards. We kept the line listing, we put up in our tent every day at eye level for everybody to see as they came in and went out. We didn't do that with a number of people who died psychologically not possible for me. But it was about half as many people died and no one got any intravenous fluids. It wasn't an option. Nobody got any measurements of potassium or sodium or hemoglobin or creatinine or kidney function or liver function. It wasn't an option at that time. But that many people survived. Mostly by having stronger patients help the weaker patients by controlling the vomiting and diuretics we can do with FDA approved drugs around the clock. That was what we did, it was different and by giving oral rehydration salts, glucose, sodium, potassium just like for cholera as it was very much. So I think the last thing I wanna say is I think it's very, very important to balance the risk of drawing blood on each morning perhaps over just several days to measure the potassium. Patients live or die quickly with Ebola. If they live seven days they're much more likely to live become what I call pre-survivors to get out of the steering hot tents. To become pre-survivors to be able to take care of themselves then they can go back into the tents and help the people that can't get out. So if you can measure potassium for just a few days you can save more people's lives. So for me I'm wanting to take that risk and drawing the blood. It really makes that much difference. Thank you Dan. We're out of time I apologize. Some of us will be able to stay on beyond the conclusion and converse further with those of you. But we're at the end of our hour and I think we're gonna need to close. If you have any closing thoughts about where we're gonna be by the end of the year that would be helpful. Just a little bit of looking in the magic ball given all of these uncertainties but we have a lot of promising things happening. Why don't we start with Jean and just go down. It's closing thoughts. I don't know I bet on the Seahawks to win the Super Bowl. So I mean that'd be a very good predictor. I do work for Paul Allen. So you're gonna pass. You know I've seen various models and talked to some and some have indicated that if we can diagnose within the first 24 to 48 hours of symptoms that we can get the outbreak under control and drive it down their models. So I don't know I think with the availability of some of these diagnostic tools some of them that are highly field deployable I think we should have some optimism but again I think we need to be very cautious and again as I said earlier not get complacent. Thank you Michael. I think every outbreak an important component of the after actions is to take away some lessons that we can implement for the next time. And I think there's been quite a bit of effort focused on being able to do that in this particular outbreak. Diagnostics I think is one that has received a considerable amount of attention not only to be able to address this outbreak but I think will place us in a position in the future to be able to better respond more quickly to other outbreaks that I fully anticipate will occur with Philos as well as a lot of other things that we haven't yet even thought about or considered. Rosemary. I think that diagnostic technology will continue to improve and evolve. I started as a clinical microbiologist many years ago and the technologies that we use today were not available. And so I think building on all of the lessons learned it will inform how we improve technology but also a greater understanding of the challenges around the fact that you can't have a diagnostic ready 20 minutes after an outbreak starts. Thank you. So please join me in thanking Gene, Michael and Rosemary as well as Sally and Andy. Thank you both for sharing. Please join me in thanking them.