Thanks to all of you for coming to the center for global job today for this discussion of tension the tension between i think that sound effect is appropriate when i say the tension. For the tension that might exist between the need to deliver humanitarian care when thereseh an outbreak as serious as the recent Ebola Outbreak, and the need to actually learn, learn what works to address thatre outbreak, especially in the case where the outbreak is of a disease which is emerging, for which at therapeutic does not exist and even a vaccine doesott not exist. Anin those cases the need forhe learning is really quite acute ear but how can that need for learning the accommodated when the humanitarian needs is son nd great . So our speakers today who will be addressing that point are the leaders of a team at the National Academy of science who produced a report just recently published on the topic of inflicting Clinical Trials during epidemics. Im going to turn over the podium now to the cochair ofpodn that team who is doctor gerald keusch, currently professor at a Boston University and is also managing a very important and exciting institution that is resulted been created their where one can do research on emerging and dangerous diseases. This is an institution which we desperately need in the United States and is working hard to try to bring that to fruition. He and his copresenter david peters will be talking for about 15 minutes each and then will have a Panel Discussion during which we going to welcome doctor carrie teicher, the you maintain group that actually did most of, did more health care and save more ebola lights and any other single group during the Ebola Outbreak and also Jeremy Konyndyk who was you with us at cgd and who supported the United States effort to control the ebola epidemic from his position as director of our emergency, what is it, the office of u. S. Foreign Disaster Assistance at usaid during that time. So now ill turn it over to gerry. Jerry. Thanks, mead. And my thanks as well to everybody for participating and for those of you are watching remotely. We are really grateful for your input. Im representing, and with davie as well, representing a committee that was formed at the National Academy of medicine too look at the issue of doing Clinical Research when there is an epidemic, and there were a multiplicity of issues that were present at the start of the outbreak. And so critically as mead said, especially for ebola, there was actually very little that was dont buy how to manage a patient with ebola. Just plain clinical support. And there were no therapeutics or vaccines that had gone through human Clinical Trials and shown to be both effective and safe to use. So thats sort of the genesis of where this committee began. Ill tell you a little bit about that. What david and i are hoping to do today is to hear from you, to get some of your thoughts, and particularly around two other questions. I dont think we need to delve t into the technical aspects of statistics and study design, but how do you in fact, integrate research into an epidemic response . I think we are past the time when we would say does that need to happen . P i think we now know clearly that has to happen. The question is how. And then secondly, how do you create the overall governance and Leadership Structure thatgon can address this kind of an issue, and what might be the criteria . So i thought it was worthwhile to back up just a little bit to some fundamentals of how to develop new drugs and vaccines . And the same thing could be said for diagnostic tests, except the issue of human safety is not really as significant as it is for drugs and vaccines. So first you need the site. You need to figure out whats a target for a drug, whats a target for an immune response and a host, whats a molecule and a pathogen that would beberp useful for the same thing was applied to diagnostics. And now you have to find that r d. Fund. A lot of that is funded of this upstream basic research is funded i public money. The Development Process is something thats done by industry, and particularly in this country. But you need to determine ultimately whether these things work in humans. We start with animals, and thedm fda has often applied a too animal rule where you need to show both safety and efficacy in two different species. And thats in part because response to say a single drug or a single vaccine may differ according to what species you are in. And showing your work into animals doesnt say works in humans or that is actually safe in humans. When you have several data from animal studies, you can get Regulatory Approval to start a phase one trial in humans, which is a small study, usually a dosing study, looking for safety primarily. These are not people who are at risk of the infection or might need treatment. If you can show that it is safe in a smaller study you can move onto a larger study which looks at both safety and a Larger Population as well as an indication that these perform as you expected, that a vaccine will produce an immune response that you think will be protective. And then ultimately if all of that goes well and something is licensed and introduced, as three trials are larger scale and we really begin to look at the efficacy and get much more safety data. Safety and most of the candidates that enter into the process fall off for one reason or another before you get to phase three and even the result of the phase three. So one of the questions that might be asked is, why is research during ebola different than other things that weve done in the past . Cholera, dengue. First thing is high mortality, no proven treatment, and experimental human infection models are not possible. You can do that with cholera because we can treat you if you develop the disease, and thats been done. Human models of cholera to develop vaccines. For this kind of an infection like ebola, and outbreak is the only opportunity for human trial. Op measles, as we know, has a highly safe and highly effective vaccine. H cholera we know how to treat, and antibiotics can eliminate the organism and short of the clinical course and is now ready a cheap and effective vaccine. Not yet bernanke, but its not for dengue but is nott difficult to conduct trials during baking a large embers the patient all the time and dengue is typically not a lethal and disease. So a bowl and diseases like it stand out as different. Out is. Why do you need to do research during an Ebola Outbreak . The first of Clinical Data to learn how to best care for infected patients. Im a physician. I look at what we do is appoint with two sides. One side is taking care of people. The other side is learning how to do a better than those to me are inseparable. Constant learning is part of the model of being in the health care profession. Drug vaccine for safety and advocacy in humans because animal models in general do not reliably predict the human response. So you actually have to go to the human trials to show that it works and its safe. If you had good vaccines you would be able to use them to enhance the Public Health approach and use it to prevent future outbreak and when it fails to prevent an outbreak and you have people that are sick, you need to be able to treat them and treat them effectively and the addition of drugs to the higher standard of Clinical Care in maybe a significant improvement in survival and reduction and consequences. So this part of advancing medical knowledge in general and patient care and this is what the fda says about Clinical Trials and why they are needed, clinicians dont know if and how well new approach will work on people, if there are several, which of them are better, are there subpopulations in which one or another the treatment will work and whats the context, whats the setting. You need that kind of information before you can approve and license something and manufacture it and distribute and use it. And to rapidly as possible approaches. We say that Clinical Research is not necessarily for the person thats involved in that clinical trial, its certainly for the future. It is potentially available to individuals who are themselves suffering from the disease if the progress can be made and shown to be beneficial. So sum up Clinical Research that was done during outbreak, wewe learned very little definitively and because of that, the National Academies were asked to assess the trials and recommend improvements during future emergencies, sponsors with three parts of the department of health and Human Services from the assistant secretary for preparedness and response, fda and infectious disease, thehe academy created 16member from the u. S. To europe and africa, we had three public workshops. We had sixclosed committeeor meetings, very comprehensive literature, review, conferenceli calls, email exchange and incredibly external and internal review process before the report was issued. Basically the context of the outbreak was actually its thought that patient zero was a 2yearold in ginny, in rural ginny who became ill in December December 2013 by the middle of january the trail of cases frome that child to to relatives and some of the Health Care Providers resulting in similar kind of death was recognized aso unusual. Unusual something and the medical officer out in the boonies in ginny notified the administry of health and they came to the conclusion that it was coolor. That shouldnt have been on their mid because the stool is bloody. They did not identify it and it wasnt until the latter party, we are worried this may be Something Different and they asked nsf which was doing work in the country to come and take a look, nsfs response was immediate and strong and they said, this looks like a fever, sent it to france and diagnosis was made in the middle of march. Last two months from the point at which an outbreak was identified and that was really important because at that point already it had crossed the borders into continuous countries. Mff now came in and built an enterprise to take care of patients and they quickly recognized that this was out off control, it was different from anything they had ever done with ebola and they kept saying, thim is different, this is different. At least influenced by past experience with ebola which is smaller contained outbreaks that are relatively easily controlled. It did not recognize, did not agree with nsf. They declared this as a moderate event in their language it is level two which can be supported by the Country Office andice an regional supervision, it didnt get the Global Recognition that it need and it wasnt until august that the highest level of concerns, Public Health emergency of International Concern was declared by who, nol the International Response started again and only then was the possibility of doing Clinical Trials and now six months had gone by and the thousand effective people which had never been seen before in Ebola Outbreak. So ultimately there were over28,000 infected, over 11,000 died. At the beginning no approved vaccines or treatments and then in august or september of 2014 when you started thinking about Clinical Trials, things start today come out of the woodwork, 20 potential candidates that could have been studied. This is the timeline of the outbreak in terms of cases, and so the three lines here are the three country, target countries, here is the middle of march, ebola is declared, here is when this International Concern was raised by w. H. O. And now the response and outbreak start to kick in. Its sluggish and its several months later before the outbreak start to come down. The trials that were done, this is a their therapeutic trial and there were a few cases and that had major implications for the results that we were gaining and here are the results, there were five therapeutic trials none conclusive that would work and safe. One of the trials suggest efficacy but not going to be sufficient for convincing a Regulatory Agency that this isia okay and [inaudible] so the initial indication was that the therapeutics were not contribute to go contributing to more mortality, but not at that point. No evidence, not from the nature of the data. From the vaccine trial, one candidate had a protective effect although it got publicized last december as 100 effective. The problem with that conclusioh from our point of view is the most appropriate statistical analysis, 60 efficacy but the confidence around that estimate span zero. So it could be coincidental and looks like its effective. It looks like it could be not effective. One promising therapeutic and one vaccine but they still need to go through Clinical Research which in ebola will be the next outbreak. Next outbreak is unlikely to be as big as this one which means that we really have to be prepared to move in as quicklyan as possible. So the Clinical Trials that were implemented here sort in january, you go from say, september, october when they start to think about doing something, getting it approved, getting logistics, it was remarkable, unprecedented andra not fast enough. And so thats the key lesson. Is that we have to be event more effective and efficient andgot faster. The conditions on the ground and carrie may talk about this were really chaotic and because of that, if you focused on the people that were sick and dying and their families who were at risk, that was sitting right in front of you as something of importance, why are we going to get involved in trying to do research, particularly because you had to deal with patients and protective equipment under ambient conditions that made it very difficult to provide health care and let alone having investigators there collecting the data. Theres no consensus on what the study or how to organize it. Very limited experience with ebola. They didnt really have recognized ebola, although it turns out from the virus was, in fact, in west africa. It may have been impuring and unrecognized and unrecognized is unknown. There were real big mistakes in how the messaging was done, there was a failure to engageen community and process and some of the experimental therapies were used to expatriots that were from africa. T they seemed to do pretty well, mortality was very low andpr suddenly there was this magic medicine, magic certify uim serum that was given to foreigners and not africans. And Research Groups themselves were poorly coordinated and competitive to get their product into a trial. It was no mechanism to triage which are the most important things to do and how to do it and that was particularly true with the cases dwindled. Search is necessary and best way to ensure that it can be done under these kinds of circumstances is integrate it into epidemic response. We think these can be organizedo to work together, the question is how do you do that. Thats the challenge now. Questions were raised about the ethics of doing randomized trials, the analysis of the report is clear. It is both ethical and it proves to be feasible to the randomized trial, what you need to do is prepare the community to engagement to be able to participate. And if the research is going to be useful at all, it has to be scientific rigorous and designed in a way that would produce useful information. This kind of plans and organizing begins an outbreak occurs right now and requires international and National Coordination and collaboration and across everything, local Community Participation in the process is actually essential, not only during the epidemic but before the next one happened. [inaudible] happens. You cant do the research about it, but it also the community as a part of the effort, so excluding them makes to delete a separate increase adverse conditions trying to do it. The various capacity to do Clinical Research, but the key message to the key part of our message was pseudowant to separate the Research Establishment and agency going into liberia and building a beautiful award in a decrepit hospital where the level of Clinical Care is awful. It has to be across the spec to a Public Health and respond in the Clinical Research. These need to be linked together. Investment is needed now to start moving towards this kind of prepared processes and engage in coordination among the research and Development Agencies to cover the whole broad agenda is critical and how do you get the optimal leadership to do this . It may be different with Clinical Research then if youre trying to do a rapid clinical intervention. So that is the setup of my remarks for this broader picture of what was going on, what it means and why its necessary. Now if not quite apparent. David is that hopkins and is the chair of the department of International Health really has great expertise on these issues. Hes going to raise some of t