Dr. Susan Ellenberg is Professor of Biostatistics, Department of Biostatistics, Epidemiology and Informatics , Perelman School of Medicine at the University of Pennsylvania, with a secondary appointment in the Department of Medical Ethics and Health Policy. She was the hair of the International Prize in StatisticsFoundation that will be awarded at the World Statistics Congress in July 2017.
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John Bailer : It started with the death of one infant in late 2013. It was followed by the deaths of family members and health care workers and healers in 2014 and exploded into the awareness of the world as thousands were affected in 2014 and 2015. Almost 30-thousand people contracted the disease and more than ten thousand died in the recent Ebola virus outbreak that struck in Africa. How do we respond to such a crisis? How quickly can drugs and vaccines be developed, tested and distributed in the time of an emerging epidemic? Conducting clinical research studies in the context of emerging and potential epidemics is the focus of this episode of Stats and Stories, where we look at the statistics behind the stories and the stories behind the statistics. Stats and Stories is a partnership between Miami University's Department of Statistics and Media, Journalism and Film as well as the American Statistical Association. I'm John Bailer from the Department of Statistics and I'm joined on the panel today by Steve Siff from the Department of Media, Journalism and Film. Our guest today is University of Pennsylvania Professor of Biostatistics, Susan Ellenberg. She served on the committee on clinical trials during the 2014/2015 Ebola outbreak. So Susan, how did you get involved in questions related to health interventions for epidemics?
Susan Ellenberg : I've always been interested. I'm a clinical trials person that's been the focus of my research throughout my career and I have been on a couple of committees of the National Academies of Science, was National Academies of Medicine, actually used to be called the Institute of Medicine on these topics. I've also always been very interested in the ethics of clinical research and have written about issues there and so when I was invited to be on this committee of the National Academies to look into what happened during with research efforts during the Ebola epidemic, I was very excited to be invited and I joined the committee.
Steve Siff : What did you find when you looked into the research efforts?
Ellenberg : There were...was a lot of debate. At the beginning if you remember back in the late middle mid to late 1980s, there was similar angst with the AIDS epidemic, where people were dying and everybody was fearful and people were anxious about how to proceed. So with the Ebola epidemic there were some similarities the epidemic was growing very quickly. There were some organizations that were very anxious to find the best way to treat people or to prevent the disease. There were no known treatments for Ebola, no known antiviral treatments or other kinds of treatments that were known to be effective; no vaccines certainly and there ended up being differences, strong differences of opinion, as to the way forward, with some groups feeling that they just had to really focus on treatment trying to do their best in dealing with the epidemic trying to prevent people from being in close contact with people who are infected and other groups including the National Institutes of Health feeling that it was essential to try and learn during this epidemic what treatments might actually work; not just throw anything that you could think of at people without really having any idea about whether they worked or not. So as a result of these differences of opinion, different kinds of studies got started. Many of them...most of them were single arm studies looking at drugs that had that were available for other purposes or new drugs that a company was making available, whereas groups like the NIH were trying to set up randomized studies. So there wasn't a lot of coordination or collaboration among the different groups all of whom were doing their best in trying to help.
Siff : So from a statistical standpoint was the problem one of reading control groups to test these various unproven remedies against?
Ellenberg : Well I think the debate was whether or not it was appropriate to have a control group. There were some who felt that the only ethical thing to do was to give everybody whatever treatment that you could possibly get your hands on that might possibly work. Others took the tack that well let's start by giving everybody a treatment and then if it's not obvious after a small experience that it's working or not working, then we'll go to a randomized study. And other groups like the NIH wanted to start randomized studies from the very beginning. There were different approaches to... different issues to between the treatment trials and the vaccine trials...and one of the approaches to the vaccine trials which did involve randomization was very innovative, though it was a cluster design where they identified each new case they identified. They created a cluster of people who lived in the community of that case or they were closely connected with that case and then they randomized those clusters to either get that vaccine right away because there were some vaccine candidates or not for another three weeks. So again, it wasn't a full randomized, it wasn't a long term randomized study but they did randomize for immediate vaccination versus delayed vaccination and because they felt that they what was known about the disease was that people who are exposed would likely show signs of the infection right away. So they were very different issues with the vaccine trials and the treatment trials.
Bailer : Some people listening to the program may not know the technical terms that are being used. So just describe what a clinical trial is, and also the distinction between a single arm and a, you know, a different type of study designs just to give some sort of a broader communities' perspective..then they'll have a broader perspective on this.
Ellenberg : Well, a clinical trial is any study where people are treated with an agent that's experimental for that particular condition that they are being treated for. If it's a single arm that means everybody's getting that treatment. There's no comparison group; there's no control group. A randomized clinical trial is where on a random basis half the people are assigned to get the treatment and another half are assigned to get whatever treatment is given to the control. It could be a placebo. It could be the best standard of care.
Bailer : You know, I was curious about the idea of trying to conduct a randomized trial where the Ebola outbreak was occurring. What are some of the challenges in trying to do research there?
Ellenberg : There were huge challenges and of course, that's what many people felt that those challenges would be impossible to overcome. The biggest challenge was the lack of health care infrastructure...that there weren't the hospitals, there weren't the trained physicians, there wasn't the equipment. People who were treating these patients needed to have very protective equipment that would keep them from getting exposed to the virus and at the beginning when that equipment was not available, many of the people providing health care...physicians, nurses...they got the infection and they died. All of that had to be set up and brought in. It was very complicated. Even the issue of data collection was problematic. The electronics were not what we have here. A lot of the work was done on paper. People were collecting information. They were writing information down on paper in the room where people were being treated. They had to worry about, you know, whether that paper was going to carry the, you know, the virus with them when they when they brought it out. The challenges were just enormous.
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Bailer : You're listening to Stats and Stories, where we discuss the statistics behind the stories and the stories behind the statistics. Today, our focus is on studying emerging diseases...particularly epidemics. I'm John Bailer from Miami University's Department of Statistics and I'm joined by Steve Siff from the Media, Journalism and Film Department. Our special guest is Biostatistician, Susan Ellenberg. So Susan what exactly do you do as a biostatistician on a clinical trial?
Ellenberg : The biostatisticians who worked on these studies try to develop designs that would provide reliable information but would be applicable in this kind of setting...and there were a variety of designs that were used.
Bailer : Can you say more about what do you mean by design?
Ellenberg : Well the way the clinical trial would be conducted, so if you're doing a study, you're just trying to...you're just using a particular treatment and you're giving it to everybody. What can you learn from that? If everybody was dying beforehand and then you start using this treatment and then everybody gets better very quickly, then I think you can draw a conclusion that this treatment is effective. People always use penicillin as an example of that. Back in the day when penicillin was first evaluated, you didn't need a control group because the difference between what happened when you gave people with infections penicillin was so different from what the natural history was before that you could easily conclude that it was effective. And that's what people were hoping to find with the Ebola situation. They really did not want to leave people untreated. They were hoping that whatever they were using to treat patients would be so effective that it would be obvious. And unfortunately, that was not the case.
Siff : When you're designing these studies, I guess there are two risks? Is one risk that you don't discover the effect as quickly as you might?
Ellenberg : That's right. So you try and design these studies so that you can identify a real effect as quickly as possible but that you really have some reliable way to evaluate the effects. So let me give you an example. One treatment that's not a drug but just rehydrating people; giving them fluids that was very important for something like Ebola because when this infection people are losing fluids. They have horrible diarrhea and they're vomiting and they're losing fluids so you have to replace the fluids. Now in places, once they started using the fluids, which again is not a drug, is known to be useful in this kind of situation, the mortality went down. It didn't go down to zero but it may have gone down from say 60 percent to 30 percent. So once that started to be used, then it made it more difficult to see whether the drug that you were giving, you know, was really doing anything. What the NIH did, they implemented clinical trials that were randomized trials where half the people got a drug that they wanted to study. The other half got best supportive care which included the provision of fluids and then that was controlled for...and then they would be able to see whether the drug did anything good over and above the effect of the of the supportive care. And that's really the most reliable way to get an answer.
Bailer : So did it?
Ellenberg : Well now, here's another problem. By the time these...we talked in the beginning about the difficulties of implementing these studies in this kind of environment. Well because of what the work that had to be done to get the studies ready to go, the studies didn't get started until the epidemic was already on the wane. So they were not able to get enough patients enough people to be in the studies to really definitively show whether the treatment was working. It looked promising but the results were not definitive in that study. But there were no treatment results of any studies that were definitive because most of the other studies, I think all the other studies there was no control group...and there was no way to tell whether people did better or worse who got this drug. And that's a very important point because however horrible this disease is, not everybody died. And what you really don't want to do is to make things worse and that's one of the other important reasons to have a control group. Even when you have a terrible disease. You don't want to increase the mortality from 60 percent to 80 percent and when you're testing something for the first time, you know, you don't know that that's not going to happen. I have a cartoon that I use in my clinical trials class and it shows somebody inviting, a physician inviting a patient to be in a clinical trial and the patient says only if I can be sure I'm in the placebo group. And that's the whole point. You don't know whether you're going to improve things; you don't know whether you're going to make things worse. And that's why those of us on the committee or that's one of the reasons that those of us on the committee thought that the comparative clinical trials from the very beginning was the best approach.
Siff : How effective are the most effective treatments in the Ebola epidemic?
Ellenberg : Well it's pretty sad. None of the studies show definitive results. So we don't know whether any of these treatments are really effective and that means if there's another outbreak, we're not going to know what to use.
Siff : Now are you confident that it's the drugs that that failed here? How do you know that the studies didn't fail?
Ellenberg : We don't know that the drugs don't work but we don't know if the drugs do work. That's the problem.
Bailer : So how do we prepare for the next Ebola epidemic?
Ellenberg : Well that was a big part of this effort from the National Academies of Medicine to say, how should we proceed the next time. One of the big issues of course is the infrastructure. We need to improve the health infrastructure in these countries. That takes resources. That's problematic. But without a better infrastructure, it is going to be difficult to do a lot better the next time.
Bailer : So what does that mean to say when you're improving infrastructure, what would that look like? What does that mean?
Ellenberg : It means improving the hospital facilities; the places where you would be able to treat people with the equipment that's needed; to protect the caregivers; to have trained people there who are already ready to be brought in and work and treat. Another big issue is engaging the community; having an increased understanding of medical research. As you can imagine, many people in these communities, they were petrified by this outbreak and they were not sure that they trusted these people coming from elsewhere wanting to try and do this and that; and disturbing their standard practices; their burial practices. They had very strong feelings about this and they were told they needed to isolate people; not come and visit people in their family who were sick; not bury their dead. The dead had to be, you know, had to undergo cremation to make things safe. These were all very difficult things for the community to absorb. So there needs to be a lot more engagement with the community and bringing in people from the community at the very beginning who can work with the researchers to be able to explain to the community what needs to be done.
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Bailer : You are listening to Stats and Stories and today we are discussing the design and analysis of clinical research for emerging epidemics such as Ebola. From the general audience perspective for this show, how can they best understand the importance of the kind of work that was done on this committee?
Ellenberg : You know most people had heard about the Ebola epidemic. It was big news. It was big news in our country and in other countries. We knew that there were people from here going to the regions that were suffering with the epidemic to treat people and some of them got infected. Some were brought back to the US and I think we should make people aware of the importance of epidemics elsewhere. It's not a so this is not our problem...this is our problem. And epidemics somewhere else in the world can come to the US. We're dealing with Zika virus now. We know that AIDS originated in Africa. So we need to be prepared here to work with people in countries where these epidemics are likely to start so that we can do better next time and we can fully test treatment approaches and develop optimal treatments and vaccines. I do want to talk a little bit about vaccine research because that presented different issues than the treatment trials. When you're using a vaccine, you're using it in healthy people. So the idea of doing a randomized trial in people who are not infected yet, did not appear so ethically problematic to people. There wasn't an immediate urgent need. And so, the NIH did not have problems setting up and they did set up a large vaccine trial, which again was set up as the epidemic was waning, so there weren't enough people who ultimately got infected to be able to know whether the vaccine was effective. But they were able to learn a lot about the safety of this vaccine candidate and the extent to which it did what it was supposed to do in terms of raising antibodies that would indicate that maybe it will be protective.
Siff : Logistically, what have you learned about how researchers should set up trials for the next epidemic? What would you suggest that people might do a little differently next time based on what you learned?
Ellenberg : Well there needs to be a coordinating group that needs to meet immediately as soon as there's a recognition that something is going on; and to prioritize the treatments and vaccines to be studied; and that people need to agree to work together so that you have the highest priority agents for study. People are working together to do those rather than have, you know, a smattering of, you know, this researcher wants to study this; that researcher wants to study that; and everybody's doing their own thing and nothing really gets finished. So that's one of our strong recommendations is that at the very beginning, an oversight group is convened and will prioritize what's to be done and people will have to work together to get those done.
Bailer : So who's going to be the referee? Who is going to be the referee for such a such a discussion?
Ellenberg : You know, that's not entirely clear. There are some organizations we discussed in our group. There's the World Health Organization. There's a new organization that's a conglomerate of researchers and people working in industry who can put things together. That is something to be decided. But I think there will need to be some clear leadership that can take things from the very beginning and get people together. The WHO tried to do that the last time but it didn't get started until later in the epidemic and didn't really get everybody to agree on how things should be done. So it wasn't as effective as it should have been.
Bailer : So I'm curious, you mentioned earlier that one of your interests or the ethics of clinical research. I was wondering if you could talk a little bit about what are some of the ethical considerations that have to be examined, considered and evaluated when you want to conduct clinical studies?
Ellenberg : Well the ethics really were primarily around the treatment trials. As I mentioned there were people who felt it was unethical to have a control group. They couldn't imagine, for example, if you had a family where more than one person was infected; that one person might get the treatment and one person might get a placebo or not get the treatment. They felt that it would be, you know, was unethical to do that. Whereas other people felt the most ethical thing to do was to give everybody an equal chance to get an experimental treatment versus best supportive care because you didn't know which one was going to be best. You didn't know if that experimental treatment was going to be helpful or harmful. So there was a big debate about the ethics of doing these studies.
Siff : How do you answer that debate? I mean those are both perfectly valid positions. How do those get resolved?
Ellenberg : Our committee felt that the best approach was in fact to do the comparative study because I can get an answer very quickly. You can set up these kinds of studies with regular monitoring so that they can stop very quickly if it's very clear that you have something that's that has a very strong positive effect or conversely, if it seems to be harmful. It isn't like you have to wait a very long time necessarily to get the answer. So our recommendation is that randomized study should be considered from the very beginning. But you know, ethics are very personal kind of thing and this is the opinion of our committee. There may well be other people who feel differently.
Bailer : And I assume all these studies are having to obtain informed consent from all these participants.
Ellenberg : Yes that's another issue...is how informed consent is done. And that's something else that needs to be prepared for. You need to have community involvement in developing the ways to get consent but informed consent was in fact done for the studies that were done. I don't think that was a huge problem except that it probably could have been done better if there had been more community involvement in it from the very beginning.
Bailer : Trying to study an epidemic which has its own natural history, you know, epidemic curves go up, they go down. It seems like by the time...anytime you're trying to study something that's an epidemic, you're likely to have it over before you can start really diving in and looking at intervention.
Ellenberg : That's a big problem and it's not one that our committee really could get into because that's a question of how do you know when it's going to continue. At the very beginning when it was first declared a public health emergency, nobody knew whether it was going to peak and then go down rapidly which is what happened...or whether it would continue. When AIDS was first recognized, people didn't really understand it for a long time what the dynamics of the epidemic were. It turned out that that epidemic just grew and grew and grew. In fact, it was much bigger than we thought it was from the very beginning because at the very beginning, we saw the people who were sick but we didn't recognize that those were just the tip of the iceberg and there were many, many more people who were infected and still healthy who would ultimately get sick. So that's that's very tricky but I think our job has to be able to jump in as early as possible when we see this epidemic growing. But it is tricky. You know, you can do a lot of work and if the epidemic is gone by the time you're ready to get started with your studies then that work will be for naught. So that's an important area to go. But I think we all felt that for this time, this Ebola epidemic, we could have gotten started sooner...could have been or should have been recognized sooner.
Siff : Do the lessons of one epidemic apply to the next?
Ellenberg : I think many of the lessons do. There will be differences but I think the need for infrastructure; the need for, you know, prioritizing when there's no available, when there is no known treatments; prioritizing the treatments and getting people to coordinate; I think those are going to be relevant to just about any epidemic.
Bailer : Did you see any difference in how we responded to the Zika emergence from lessons learned from the Ebola?
Ellenberg : Well I it's going to be interesting to see what happens this summer with Zika. I think people are expecting that Zika is going to continue. It's moved into a lot of other countries and I'm not an expert on Zika but I know that there are many studies ongoing now. There are vaccine studies in place and I think the hope is that we will do better with Zika. Now Zika is quite different. With Ebola people who got infected got very sick very quickly and many of them died. With Zika, most people who get infected with Zika, don't get very sick at all. There are a few exceptions but it's not such a serious disease. It's like a mild flu. The big problem with Zika is women who are pregnant, who get infected with it and then there's a very, you know, a high proportion of problems with the babies. So I think we're dealing with something very different and the approaches will be different because you won't have this ethical issue of not rushing in and treating people who are infected. We may not may not even know who is infected because they may not be very sick. So I think the big issue with Zika is going to be to develop an effective vaccine.
Bailer : Well Susan that's all the time we have for our conversation today. Thank you so very much for joining us.
Ellenberg : Well you're very welcome. I enjoyed it.
Bailer : It's been a lot of fun. Stats and Stories is a partnership between Miami University's Departments of Statistics and Media, Journalism and Film and the American Statistical Association. Stay tuned to keep following us on Twitter or Itunes. If you'd like to share your thoughts on the program, send your e-mail to statsandstories@miamioh.edu and be sure to listen for future editions of Stats and Stories, where we discuss the statistics behind the stories and the stories behind the statistics.