Welcome to Research Ethics Reimagined, a podcast created by Public Responsibility in Medicine and Research, or PRIMR. Here, we talk with scientists, researchers, bioethicists, and some of the leading minds exploring the new frontiers of science. Join us to examine research ethics in the twenty first century and learn why
Catherine Batsford:it matters to you. I'm your host, Catherine Batsford.
Dan McLean:And I'm your cohost today, Dan McLean.
Catherine Batsford:And today we're thrilled to welcome Dr. Wilbur H. Chen. Dr. Chen is the Frank M.
Catherine Batsford:Calia, MD Endowed Professor of Medicine and a Chief of the Division of Geographic Medicine at the University of Maryland School of Medicine. He also serves as Chief of the Adult Clinical Studies Section at the Center for Vaccine Development and Global Health and director of the UMB Travel Medicine Practice. With a career dedicated to infectious diseases, vaccine development, global health, Doctor. Chen brings invaluable insights into how research can balance scientific advancement with ethical responsibility. In this episode, we'll explore the human challenge study for shigellosis, examining its place in the larger research process.
Catherine Batsford:We also have Jake Eberts, a board member of One Day Sooner, joining us to discuss his experience as a research participant for this human challenge study. Welcome to the podcast. Thank you so much for being here. So let's start with a human challenge study for Shigellosis. Can you tell us a bit more about the study in general and its goals?
Wilbur H. Chen, M.D.:Certainly. My center, the Center for Vaccine Development and Global Health, has been interested in trying to tackle diarrheal diseases which afflict impoverished populations, developing country settings, places where there is lack of access to clean water, sanitation, and hygiene for fifty years actually. We've been actually doing this, trying to develop vaccines against diarrheal diseases for fifty years. So this is the next iteration. The particular study that you're referencing is a collaboration in which we are working with colleagues at the Institut Pasteur in Paris, France.
Wilbur H. Chen, M.D.:They've also been trying to develop a number of different important global health vaccines, including a Shigella vaccine. They've been working on it also for decades. And so we partnered together and put this together to evaluate their particular vaccine candidate. Our philosophy is to advance a vaccine, any vaccine. And so we work with global partners on their vaccine candidates, as well as our own that we've developed in house.
Wilbur H. Chen, M.D.:We're an academic research institution, a university. We have some basic microbiologists that are devising vaccines, also trying to understand the pathogenesis of these pathogens. And again, we have our own candidates, but we have to have a number of vaccines in the pipeline to hopefully eventually have a successful vaccine. So we want to have as many vaccines to evaluate along the line. So again, going back to the reference vaccine study, this is a vaccine that is an injectable vaccine.
Wilbur H. Chen, M.D.:There are other vaccine candidates that are oral vaccines that you just kind of swallow and then give an immune response in the GI tract, which is where you actually get the infection. So this vaccine was evaluated with what we call a human challenge model. And that means that we take consenting healthy volunteers and bring them into an inpatient unit and infect them on purpose with Shigella. I have other studies where we infect people on purpose with other agents like influenza, dengue, other diarrheal diseases.
Catherine Batsford:Jake, can you tell us take us back to your decision to join a challenge study? I think you hear about it a lot, that things are going to trial and that they need participants. What brought you to that moment where you were like, you know what? Yes, I'm going to participate in this.
Jake Eberts:Yeah. So it was really purely by chance. I had no biomedical training or public health background, and I saw an ad on Instagram actually one day here in the DC area. Human challenges are relatively rare compared to, you know, the total body of clinical trials that go on, but there's a pretty high concentration of them here at a number of institutions and universities here. And so I saw an ad.
Jake Eberts:It was you some listeners might remember the, you know, Oregon Trail game, the pixelated one back in the day. You've got a dysentery screen. And so it was that as you have done a dysentery and then below that in that little font, like Shigella causes dysentery, help us prevent Shigella. Most clinical trial ads are eye water really boring. They don't need to register.
Jake Eberts:So I clicked on it, was generally kind of curious. I was working a full time job at the time, you know, in the office. And I had never heard of a human challenge with you before. So I vaguely knew that vaccines involved testing. I knew that there was phases one, two, and three.
Jake Eberts:Could maybe give you a generic sort of high level description of what those involved. Wasn't aware that there was ever challenge challenges involved because frankly, face value, that sounds a little bit medieval. Right? So I learned about it a little bit, threw my hat in the ring, and and I read about the disease too. I was like, wow.
Jake Eberts:I I the Shigalat that Shigalatasan slash dysentery had kind of gone with the way the pioneers. There's a, you know, quick reading pedia. It's like, you know, somewhere around a quarter million, even more at the time. I was thinking of people who die of it every year, particularly children. And so I kind of joked with my roommate at the time, this is a great way to both make some money and be self righteous about it and, like Right.
Jake Eberts:I'm off of work. So, yeah, I threw my name in the ring and they called me. I eventually decided to go up to Baltimore where the good people at University of Maryland, Baltimore started this process of informed consent and all that stuff. And so it was a it was a long, drawn out process, but it really was by chance that I that I started doing it.
Catherine Batsford:So, doctor Chen, in this whole process, where does the human challenge study fit? Are you closer to the end or, I mean, you're still looking for the end, I'm sure, but when would it, something like that roll out to the general population?
Wilbur H. Chen, M.D.:Great question. So actually the human challenge model is used in many different ways. It could be used very early on in just understanding disease pathogenesis. So again, going back fifty years ago, we didn't know what made cholera result in such violent diarrhea. So we performed human challenge studies to understand the pathogenesis of cholera, and then we're able to determine that it's the cholera toxin that the germ makes that actually results in the diarrhea.
Wilbur H. Chen, M.D.:In the case of enterotoxigenic E. Coli, it's another toxin, heat labile enterotoxin. So that's kind of, you know, the use of human challenge models very early on before you have a vaccine or a therapeutic candidate that you want to evaluate that you can understand the basic pathophysiology of a pathogen, which again, there might not be animal models to be able to understand it. So you have to use humans. That's one instance.
Wilbur H. Chen, M.D.:So another instance is that you have a number of early candidates and you need to what we call down select. Kind of pick out of the candidates that you've already developed. And you need to say, which is the one that we want to go forward because we have a number that look like they're working in the lab, maybe in some animal models, but we need to kind of select how do we pick that. And that's one way that also human challenge models can be used early on with an early candidate that might not be the definitive one where we can have a human challenge model to say, yes or no, we're gonna have this one go forward or not. And that's a little bit the space of where this study that you're referencing, where we had a candidate not so early on, but basically we wanted to determine whether or not it should go forward.
Wilbur H. Chen, M.D.:Okay. Now there's the last instance where you've got a well, candidate that maybe has gone through phase one and phase two clinical trials, and now you need to show efficacy. And efficacy studies are traditionally done in what we call field trials in large populations where you see the disease. Now in The United States, we see very little cholera, shigella, other diarrheal diseases, unless there's a defined outbreak, which you can't predict. So you can do a human challenge study.
Wilbur H. Chen, M.D.:And that's what allowed for the cholera vaccine to be licensed and approved in The US. And so we did a human. We were able to perform a pivotal efficacy study with a human challenge model as a phase three study. And this is really the most mature vaccine and use of a challenge model. And in this case, we were able to show efficacy with just the challenge model and not using a large scale field study.
Catherine Batsford:So when you explain the purpose of the human challenge studies, how do you communicate the safety protocols and what does the informed consent process look like? And I was just curious from your end, from a researcher, what the thought process is going through that.
Wilbur H. Chen, M.D.:Another great question that comes up very frequently, which is I, as an investigator, you know, my foremost kind of concern is to design and implement a study that's conducted with the safety and welfare of our volunteer participants in mind. So in other words, the consent process is one of the parts of the study where I spend a lot of time making sure that we have designed and implemented methods to communicate the risk of the study. And I try to do it in clear language as possible, and I try to do it as many times as possible. So you might hear it one time and still not remember it. Mhmm.
Wilbur H. Chen, M.D.:So I do it in an iterative way, which means that I will give an orientation talk and talk about it. They will read it in the informed consent form. And then when I meet with them one on one, even while they're in the study, I continue to communicate to them what are the perceived risks that they might encounter at all stages of a study. In the vaccination stage, there's less of a risk, although they are receiving an experimental study vaccine or the placebo. But the risk is really the highest when they are admitted to the inpatient unit and are about to encounter the challenge part of the study.
Wilbur H. Chen, M.D.:And that's again, when they have arrived at that point in the study, they have heard multiple times from myself, the study nurses and others about the risks of the study, and especially about what it really means when they get challenged. So it means, you know, they're, they're drinking a solution that looks clear, but actually has the bacterium in it and that they should expect the infection Shigella. And then I tell them what does Shigella infection look like? It's basically high fevers diarrhea that might be bloody and severe cramping abdominal pain, you know, those things combined. So I really try to not paint it in a rosy way to make it sound less impactful or less risky than it really is.
Wilbur H. Chen, M.D.:But I also try to not oversell it because I do try to tell them that we have safety protocols that are in place as part of implementing the study. So in other words, we're doing this in an inpatient containment unit where we watch them twenty four seven. There's always gonna be a nurse available and the principal investigator myself or another clinician is always immediately reachable. In fact, I sleep on the inpatient unit for the first two or three days where basically that's where the highest amount of disease illness is at that time, because I want to be there within minutes of when they are experiencing their infection, the peak of their infection, whether it be nausea, vomiting, high fevers, whatever else. And I want to be there to be able to hold their hand and talk them through the situation so that they understand that we are monitoring it and managing it.
Wilbur H. Chen, M.D.:We give them IV fluids. We give them antibiotics when they need it. There are a lot of things that are built in for the safety and welfare of the participants. So all of that is kind of the infrastructure that we have designed over many years of doing these studies to make it a standard across all of our studies that that that's the standard approach, no matter which study it is. If it's a challenge study, we are monitoring very closely and managing very closely for the safety and welfare of our participants.
Catherine Batsford:Jake, what was the consent process like? Cause I don't know anything about dysentery, and I know I would be hesitant to have yeah.
Jake Eberts:Right. So as you can imagine, for a human challenge trial, the consent process is, the consent process is pretty intense. Right? Work that I would later come to do at the nonprofit that I work at that is really focused on human challenge trials. Through that work, I've come to see a wide variety of studies across multiple countries and institutions.
Jake Eberts:Most often, they involve a quiz. Like, you have, you know, kind of a sit down session. Often, there may be presentation. You have kind of standard informed consent packet. Question's wrong.
Jake Eberts:In my case, you have to go over them with the the the kind of attending nurse. One on one time with the the PI, the principal investigator. There's a lot of time kind of built in usually in these processes because there is it's a very serious thing. Right? And you wanna make sure that people understand what they're they're signing up for.
Jake Eberts:My case, this was a vaccine challenge trial. So we were given two experimental vaccinations of this vaccine called SF two a dash t t one five. And over the course of about a month, I think, you know, two separate months separating, you know, these two, injections, and then came back, again, I think about a month or two later for the inpatient period. At any point, we could have withdrawn consent and been like, nope. Don't wanna do this anymore.
Jake Eberts:Done. Goodbye. But that was kind of the the process. And so it was it was both, you know, rigorous informed consent upfront and then kind of ongoing consent where they check and make sure, like, are you still okay with this? Doctor Chen, the staff were all very, very good about answering questions and things like that throughout the process.
Catherine Batsford:So you knew that you would get dysentery?
Jake Eberts:Everybody in the She Gallo trial, everyone got it looked basically a little shot glass of this bacteria in solution that had been grown in a lab that had been that has been used in multiple other She Gallo challenge studies.
Catherine Batsford:So how did you weigh the risks versus the benefits as you were going through the the consent process?
Jake Eberts:For me, it was mostly so I had a kind of I have, you know, baseline pretty high trust in the medical research system. I think that's something that is probably not surprising. But for me, I read about the disease. I read the Adborn consent form. And what I came to learn is that these studies have been done many, many times using this pathogen.
Jake Eberts:This pathogen, Shigella flexori or Shigella flexori is, you know, not antibiotic resistant because that's the point of having this kind of standardized pathogen sample you use for the challenge. Like, there definitely are antibiotic resistant strains of it, but this strain in particular, again, growing in the lab, very controlled. They knew that it would respond to the antibiotics that we would be given. And so that was one thing. And so really the risk for me was that the I had no risk of, like, death.
Jake Eberts:I knew we were we were, you know, extensively screened for markers that would perhaps predispose us to longer term complications, it was a question of, you know, is this worth the time and effort and probably pain and discomfort that will involve the the centurion I can tell you from personal experience now is not fun. And then I read Apple and so proud of having done it, would do it again, but it was some of this, the most sick I've dumped in my entire life up until, you
Catherine Batsford:know Wow.
Jake Eberts:That's far in my life. And so for me, the risk was a lot of it was logistical. It's like I had to take time off of work. I had to, you know, arrange my schedule, something to get to take care of my dog, all that sort of stuff. And so, in addition to risk, there are bunch of other considerations there.
Jake Eberts:But for me, was a question of, do I trust this research institution to keep its word? And do I think I have a decent understanding of what's gonna happen? And the answer was yes, on the informed consent process and research I did on my own. And it was frankly relatively straightforward for me that I wasn't concerned about the riskiness per se. I was more concerned about a lot of peripheral sort of, this is gonna be a lot of time, and it'll probably not be fun for those two days or three days that I'm sick, sick.
Catherine Batsford:Thank you. Thank you for participating. Doctor. Chen, from your experience, what strategies help build trust between researchers and the communities they serve? I think that could go further.
Catherine Batsford:But the trust building that you're doing within that moment with your participants is enormous. Is there a way that you could build that out further so that general populations understand
Wilbur H. Chen, M.D.:the thought and commitment you have to it? Yes. So I think, another thing that we do as scientists that do these challenge studies is that oftentimes when we're doing a new type of challenge study, say for example, Zika, when it came out in 2014, that we started talking about the possibility of performing challenge studies in an open forum. We had a public workshop and we had ethicists and other scientists that participated in the discussion before we even designed the studies. So we have these kind of scientific forums in which we can discuss how we even put together these challenge studies.
Wilbur H. Chen, M.D.:Then when we do these studies, you know, part of the standard approach is that we have an institutional review board, a local ethics board review our studies and approve them before we embark on doing the studies. We also spend a lot of time trying to make sure that we sensitize our study participants to what, what it is. And again, that's part of what I said before, which is basically informing them fully of what the study entails, which is from the beginning, when they get enrolled, what it means to be randomized, what it means if they receive placebo. What happens when they get challenged? What happens when they get discharged?
Wilbur H. Chen, M.D.:And then again, what happens if they decide to withdraw at any point in the study, which is, these studies are voluntary. They're not compelled to stay in the study the entire time. So they may voluntarily withdraw at any time. And what does that mean to them as well? Because they may have questions about, do they have have any health concerns that they need to be concerned about if they withdraw early from the study.
Wilbur H. Chen, M.D.:So we guide them through that. And that that I think is part of the kind of discussion that helps to build the understanding and respect that we have for our participants.
Dan McLean:Jake, if I could jump in for a second, I was curious that you talk about your decision to participate in this research. What about the process help build that trust for you and what could the scientific community continue to do to help future participants also have that feeling?
Jake Eberts:Yeah. And I wish I had more trenched sort of insight on this. I have a baseline, very high, like trust in the medical process and my father was a doctor and I have, especially after the pandemic became very, very more acutely aware of how critical vaccines are in terms of protection of public health and alleviation of suffering caused by disease worldwide. So, I went in, and I knew the University of Maryland was a good institution. I read the Wikipedia page and didn't see any major outstanding scandals about, you know, horribly, horribly experimenting on people.
Jake Eberts:And so I I I think that's substantively what it came down to was that baseline level of trust. But even then, I I think you don't need to have that kind of really high level of background context. You could still, through interaction, mean, just the day to day interactions with participant with, the staff and with the PI were really, really helpful. Like, everyone there was very informative, very kind, willing to answer my questions. And that was also built a lot of trust.
Jake Eberts:And then I would say, guess that was probably decisive insofar as if that had not been the case, I would not have signed up. Like, if I felt that staff were rushing through or being disrespectful, regardless of my background level of trust for medical science at large, I would not have felt safe doing that for a particular study. For me, I think the answer comes down to personal interactions with people. Like, getting people in the door in the door, might be difficult, but making sure that you're, you know, being kind and being willing and and treating people as individuals. But I think most centers do a decent job of, but I've only been you know, I only have my limited range of experiences here, so I can't say what the standard is elsewhere.
Dan McLean:And I was also interested in what the reaction of your friends and families may have been to your decision to participate.
Jake Eberts:Yeah. So as you might imagine, a little bit of a like, oh my god, what? You know, I've never like, I, you know, my father was a doctor, my family is very pro vaccine. And so, you know, after talking through my parents, and, you know, they were supportive, if a little wary in the way that you might expect for parents. And for friends, I think that, you know, my kind of dark sense of humor in general is a little bit disarming in some ways.
Jake Eberts:But like, yeah, I'm gonna get dysentery for body. Like, it is a, you know, I would explain it being like, look, it's a really intensive process. This has been done many, many times for different diseases. Like, this idea itself is not so, you know, medieval or insane as it might sound face value at first. Yeah.
Jake Eberts:People were generally, like, I say, bemused, but supportive. And and sort of one of those things kind of how I feel this way about many professions, where it's like, I'm glad someone's doing it. I'm glad it's not me sort of thing. I would say pretty supportive and and a little bit sort of weirded out.
Catherine Batsford:How important is it to ensure a diverse population participates in the human challenge studies?
Wilbur H. Chen, M.D.:Well, I think it's important that we have diversity such that we are representing the general population. When we perform these studies, we want the study results to be generalizable. So for example, if we had a vaccine and we only tested it in a white population, And I were to say to an Asian, I'm an Asian myself and to, you know, I think that this vaccine is effective. And then they ask me, well, what's the data in Asians? And I say, well, we haven't actually haven't studied it in Asians at all.
Wilbur H. Chen, M.D.:That's kind of on me as a scientist. It doesn't look good that we have failed to evaluate it in a more generalizable population such that I can say with confidence the safety and the efficacy of the vaccine. So I think that, you know, that's my interest to try to make sure that the populations that I'm studying are generalizable, such that I can make statements about the overall safety and efficacy of the product.
Catherine Batsford:Do you think a better understanding of the compliance and review process would help foster more trust in vaccines and the general public.
Wilbur H. Chen, M.D.:Compliance review process, is that talking about the FDA or is that talking about like a IRBs? I
Catherine Batsford:think the IRBs they're, they're incredible. The work that they do in my mind.
Wilbur H. Chen, M.D.:Right. No, I agree with you. I think so the local IRBs for the ones that have oversight over academic centers that perform challenge studies are well acquainted with the challenge studies. They probably had to have a learning curve, but the academic centers that are involved with challenge studies are only a handful. So that means only a handful of IRBs are probably well equipped, well versed with reviewing challenge studies.
Wilbur H. Chen, M.D.:And I think that again, part of that expertise has to be built up such that the IRB feels comfortable and confident that they know that the study has the safety and welfare of participants in mind that that the ethical framework of the entire study has been fully thought through. And that confidence means that they may ask for more justification Mhmm. More background, more rationale as to why we're devising the study this way. But a more experienced IRB would certainly already understand the rationale, the background, etc, and be able to more readily review the protocol itself. So that's where I think it really helps to have an IRB that's experienced.
Catherine Batsford:Yeah. And do you think there are any misconceptions even among researchers about the IRB process? Are there ways that they could approach it differently from the research angle?
Wilbur H. Chen, M.D.:Yeah, I think that there are, scientists and researchers who perhaps have never even heard about challenge studies that might be shocked that the scientific community is engaging in this and that we're doing it willingly and that IRBs are allowing us to do it. I think that not all scientists have heard of the rationale, the deep background, the ethical justification and framework that has been developed and well established for many decades that allow us to do this. So I think that again, are many scientists that are just not aware of this. It's a niche field perhaps. And, I'm not expecting that all scientists do understand this and are familiar with this.
Wilbur H. Chen, M.D.:So I fully expect it, and I'm always prepared to discuss it. You know, I I think that, again, oftentimes people are surprised that it's been done for many, many years and that that there are, you know, publications that talk about the ethical framework and the perspective or the risk and the benefit for why we should be doing these challenge studies. So I think probably during the COVID pandemic again, we went through that experience where again, the scientific community was talking about child studies. So we went through that again. And so I expect that we will continue to have this discussion, which is a healthy discussion.
Catherine Batsford:Jake, I would love to talk a little bit more about the compensation. Do you think you would have done it even if you hadn't been
Jake Eberts:Absolutely not. And that's when yeah. I like, it was you know, I was inpatient for a getting experimental vaccine, one that had been, you know, shown to be not terrible. You know, early phase one studies, nothing no terrifying coming out of it, but still a very early stage medical product is one thing. And then being deliberately infected with the disease that can cause really serious illness is not a walk in the park.
Jake Eberts:And that took I spent about ten days inpatient quarantine around the clock medical care and things like that. It was uncomfortable and oftentimes unpleasant. And, again, I'm, like, super proud of how they've done it and don't regret it whatsoever, but it was not, like, the, you know, trick to the amusement park. Was not fun per se. And so I think that, yeah, and this is actually when I became very, very interested in the kind of compensation debate and kind of got brought to The study I was in paid about $7,300.
Jake Eberts:And what I learned at the time through some digital sleuthing and looking at archives of the the recruitment pages was that originally they had paid about half of that or or offering about half of that. And it very quickly seemed that that did not give them enough people, and so they they increased it. And because I'm a bit nosy under Maryland law, you know, the the minutes of IRB meetings, institutional review board meetings are can be publicly requested for a couple of institutions. And so I did that. And I found that, you know, at that time, the IRB was worried that this was, like, too much money and, like, might be coercive.
Jake Eberts:In later advocacy work I did, I became very intimately familiar with this amount of with this debate over undue inducement and, quote, unquote, coercion, which I think is a really grossly and supplied term in this context. Right. But, yeah, no, I would not have done it for free. I think it'd be bravely kind of insulting to expect people to do it for free. I think that people kind of have this weird sort of view of what some researchers call research exceptionalism.
Jake Eberts:This idea that the the rule that we think about for fair compensation and treatment of individuals at economic transactions are somehow reversed when it comes to research. And so an example I bring up is authored as a construction work. Really dangerous. Around a thousand people die per year in The United States in construction. Many construction workers are undocumented, which is, you know, kind of like the most legally vulnerable category you can be in this country, especially today.
Jake Eberts:And in addition to, you know, death, there's just all sorts of horrible injuries you can get on the job. No one in their right mind would sit would, you know, go to congress or tell a meeting back to this that they're worried that people are getting paid too much in construction. I mean, this vulnerable group of predominantly many of which are predominantly black and Latino men, are being, you know, unduly induced. And in order to prevent that from happening, we need to institute, like, a national wage ceiling. You'd be laughed out of the room justifiably.
Jake Eberts:And they're like, yo, I don't doubt the good faith people who kind of these feel similarly for research. There are substantive differences between regular employment and research participation. But Holly Fernandez Lynch, who's a professor at University of Pennsylvania, has a really good article about how all of those differences still militate in favor of actually just paying people more. Right? Like, we as research participants, we don't have, you know, unemployment protection.
Jake Eberts:We don't like there's no OSHA. Right? There is OHARP and there are other, you know, the FDA, other organizations that still oversee research ethics. But this idea that we somehow protect people, especially those supposedly like financially vulnerable or lower income by paying them less to me. Really early on when I encountered this idea as a research participant, like, in the unit struck me as kind of absurd, even if well meaning, and really flew flagrantly against the kind of, like, interactions I'd had with the participants and ultimately sort of kind of led there.
Catherine Batsford:Doctor Chen, I was interested in your your take on the payment process and the ethical discussion around it.
Wilbur H. Chen, M.D.:Yep. And the way I like to say it is that I don't like to refer to it as a payment, but I like to refer to it as compensation because our participants are willingly signing a consent form and agreeing to take on risk. And with risk, there should be compensation and the compensation should be kind of appropriate for the size of the risk. So I also have blood draw studies in which I have healthy volunteers that provide blood samples, stool samples, saliva samples for my labs for their lab work. And these are not from diseased people.
Wilbur H. Chen, M.D.:These are just healthy volunteer studies. These are what the IRB call minimal risk studies. So really you're just accepting the risk of the pain of the blood draw or the inconvenience of collecting a stool sample or, or a saliva sample. Okay. So not a lot of risk.
Wilbur H. Chen, M.D.:It's the same amount of risk that you would encounter if you went to your regular doctor's office visit and had a blood draw because they had to check your your blood counts or your glucose, you know, or those sorts of things, your cholesterol, etc. So again, not a lot of compensation is offered for minimal risk studies. Now, we're talking about challenge studies. That's on the other end of the spectrum where we're asking them to willingly get infected and experience the illness of interest, which is it could be malaria, dengue, influenza, Shigella, cholera. They're gonna have that infection.
Wilbur H. Chen, M.D.:They're accepting that risk. So they should get compensated more than a simple blood draw procedure. The number of visits also because of the inconvenience of picking up their day. If they're working, they have to take off of work. All of these things have to be compensated appropriately.
Wilbur H. Chen, M.D.:So an inpatient study means that you are residing here for multiple days. So you don't go home. It's not a hotel. It's not a cruise ship. It's not a vacation.
Wilbur H. Chen, M.D.:You're there willingly allowing your body to be put at risk for science. And even though we've built in safety, we're looking out for your welfare. That is a risk and you're being inconvenienced. That should be compensated. So that's just to say that yes, there is a payment scheme.
Wilbur H. Chen, M.D.:They're getting a payment, but I view it as compensation and the ethical kind of, you know, framework over that is that I'm not paying them some arbitrary value on compensating them. And I have a rationale behind why I want to compensate them. That's that's kind of the way that I distinguish it.
Dan McLean:One note I made is this very specific number of $7,300 that there is something arbitrary about the value or the cost of giving someone dysentery. So I don't know if you had thoughts on that particular amount.
Jake Eberts:So yeah, typically when you're designing a study like this, you might propose the PI might propose the payment levels. Often, an IRB at an institution might have, you know, a little table or guidelines. They might be going off other studies or might be really hard limits instituted by the IRB. And so you'll kind of pay along with that IRBs. So the ability to, you know, reject competition is too high or theoretically say it's too low.
Jake Eberts:And that's true of a human challenge study or any sort of, study involving compensation. And federal guidelines in The United States are vague. They say that you shouldn't unduly induce someone. FDA versus other parts of HHS have different sort of opinions on what constitutes acceptable. Like, FDA considers it unacceptable to even, like, bold in the level of compensation and the clinical trial advertisement.
Jake Eberts:It's a lot of kind of patchwork. And so it's a lot of arbitrary sort of payment. I thought 7,000 a year dollars was fair. I don't think it would have been ethical if they'd been higher. I think higher payments do pose other logistical problems, sometimes, like incentivizing deceit, for instance.
Jake Eberts:But at some point, when you pass, you know, 1 or $2,000, like, there's always gonna be someone, frankly, who's poor enough for whom that's maybe unlike changing some of money. And so, you know, you're not gonna solve that problem by just, like, keeping it low. You just shift the group onto which this problem supposedly lies. So, yeah, I think it's pretty arbitrary. I've seen massively arbitrary changes across institutions.
Jake Eberts:I have sent nice but kind of start emails to institutions reminding them that they haven't updated their payments in ten years and inflation has eaten away percent. You're eating away, like, 30%. It's something that tends to fall the backburn. There's this inherent, I think, conservatism and inertia involved that make people unwilling to, like, be seen as paying two more because I think there's also stigma around it from the perspective of, like, the IRB and the the PI. Like, they don't wanna be seen as, like, bribing participants.
Wilbur H. Chen, M.D.:And
Dan McLean:to put it in context, what is the range? What is the high end and what's the low end of, participants?
Jake Eberts:Depends massively on the disease. This is something you can imagine there's not really good data for. Work we did at one day center tried to really kind of contextualize this. The highest I have seen thus far for a completed trial is around $13,000 and that was a Shigella Rechallenge. And so they were trying to figure out how different strains cross protect against each other when you've been infected.
Jake Eberts:Right? And that's an important question. Immunology, if you're designing a vaccine, what are the what is the bare minimum number of strains of of Shigella that you would want for a vaccine to have and how broad protection would that be? In practice, that means we're gonna give you Shigella once. And then, you know, a month or whatever later, we're gonna give you a different kind of Shigella again.
Jake Eberts:And so you should do this twice. And that was, I think, about $13,000 for, like, about twenty days inpatient. That's for a challenge study. Human challenge studies, tend to be at academic institutions or government body or, like, the NIH. Relatively rarely are they at private are they sponsored by a pharmaceutical organization.
Jake Eberts:Part of that is, I think, because they tend to be more relevant for neglected diseases or diseases that just have a lower, frankly, profit profile, things like malaria or shigella, things that have been eliminated in the industrialized world but still cause mental health suffering in the developing world. And so there's bluntly just not a prop as much of a profit motive. And so the author is the mantle is often taken up by academic institutions. And so they tend to pay less as well. And I think there are budgetary reasons for that.
Jake Eberts:I also think there are institutional IRB reasons for that. If you're a contract research organization for a pharma company, your job is to get butts in seats. So you are not like, you are gonna go you're willing often, I think, more to to pay a lot more. And so I've seen studies that pay 20 plus thousand dollars, and it's very clear that, like, it's sort of like the kind of consensus among ethicists is that you can't really pay for risk. The China is like more unpleasant studies or intensive ones or just involving really, you know, kind of weirdly specific profiles of people who are healthy.
Jake Eberts:You know, someone who needs to have a certain genetic marker, like, they'll pay more to try to incentivize to it. That's kind of what I was getting at when I was talking about market.
Wilbur H. Chen, M.D.:I don't
Jake Eberts:think that's inherently unethical, but it's something that is really frowned upon, particularly, I think, among academic IRBs and research activists in that sort of in in that sort of space.
Catherine Batsford:What do you think the public perception is around compensation versus the IRBs? And you just touched upon a bit of that.
Jake Eberts:I'm aware of one study in The United Kingdom that does show among research professionals, including PIs, research ethnophists that suggest there is some form of divergence there where the kind of more what I would call the standard view, among ethicists is that, like, you can't pay too much because you'll underly induce people and that's unethical. And the more, I would say, popular view among populists, so to speak, it is the people doing something important and valuable and uncomfortable and time consuming should be paid fairly for that. And that should be a lot of money. It ranges widely. I think a lot of it comes down to how you're introduced to the concept in the first place.
Jake Eberts:If I come to you saying, I did this. I was fine. I should have been paid more as a participant. People are really sympathetic. If you are sitting on a well meeting committee where you're worried about people doing something they don't wanna sign up, they they might not fully understand, you are gonna be pretty reflexively worried about compensation.
Jake Eberts:And that's a little bit of oversimplification. I think of like the thought processes involved. There's regulatory considerations. There's intra institutional competition. Do you wanna like, you know, out price this other study?
Jake Eberts:But I think that in general, people are pretty sympathetic to the idea that if this is otherwise safe and improved valuable medical research, you should pay people a lot for it because the social general the social value generated by it could be potentially immense. And it's probably and it's like generally good to pay people for the good that they produce, like the, you know, the uppercase G good that they produce. I think in general, people are pretty sympathetic to the idea. And then again, I think also still is a function of your background level of trust. If you think that vaccine research is inherently bad and that pharma companies are out to get you, you're gonna view it as bribery and you're gonna view it as like buying people off and using the bodies of the poor for, you know, the environmental research.
Jake Eberts:That's not a problem that you can fix with, like, lower compensation. That's just gonna be a background fact of, like, the nature of civic life in The United States and elsewhere at this point, unfortunately. No one actually defined what an undue influence is because it's really, really difficult to define. The broadest definition is like you unduly do someone when you offer them an incentive that causes them to either lose their ability to rationally or like to overlook their ability to rationally assess risk and benefits, maybe violate their own values to participate in something or something like that. And so but the problem is it's a very individualized like, what what is undue to you or me is very different from what is undue to someone down the road, to Susie or Sally, to whatever.
Jake Eberts:Right? It is relative to an individual, and that means you can't really craft payments to them to actually solve the problem because you'd have to craft them with knowledge of like, oh, like, can I get your tax return and figure out how poor you are, how rich you are? Because if you're super rich, then giving you $20,000 won't be that big of a deal. You know, you don't know people's personal risk tolerances. There are available alternatives in a market.
Jake Eberts:And so you can't really actually it's this bogeyman. It's this unfalsifiable thing that exists and is, I think, real to a limited extent, the one that takes this outsized position in thinking process of my research at since tracing all the way back to the Belmont before. I think what is gonna have to happen, and I hope is there is, like, movement in academia. Again, research by people like Holly Fernandez Lynch, Lee Largent, Jill Fisher, Luke Linus, like many people Emily Anderson, like many people who have identified this this really serious problem with the approach to undue inducement where you de facto end up just underpaying people who are already being in the lower end of the economic spectrum and not actually protecting them. And so my hope is that that the rank and file IRB numbers start to become a little bit more aware of this.
Jake Eberts:I think one thing that IRBs don't do I mean, and it's not their job. I have sit on IRB at a university here in DC, and it really has underscored for me how much it is detached from the day to day clinical practice, which makes sense, right, because you are a clinical trial that is. And that makes sense because it's not your job to go and then inspect on these sites that not something that the unpaid IRB can do. Failing to recognize, for instance, that recruitment problems may reflect underlying issues with compensation, stuff like that. And just being more willing to kind of think a little bit less paternalistically when it comes to compensation.
Jake Eberts:And so I think there's a gradual movement toward it. I'm not sure if there's, like, a a one size fits all measure, but that is something that I think can be fixed. And that will probably involve, like, changing the individual mindsets of members of IRBs and introducing them to the negative downside. I like the kind of negative consequences or externalities of of underpayment in terms of, like, social justice, distributed justice, and just, like, even baseline, like, recruitment, more important medical research.
Catherine Batsford:So do you think there are institutions or countries that do this well?
Jake Eberts:Countries actually, I think United States is on the better end of compensation. There are some countries. France is one, for instance. Legally, you are not allowed to make more than a certain amount of money. I think it's, like, €6,000 from clinical trial participation.
Jake Eberts:And, again, yeah. And the thinking there is and there are some countries where compensation is illegal. I believe Colombia is one such thing. What ends up happening is then you just export these trials to other places where this occurs. Very similar to discussions about, like, blood donation and blood pass blood plasma payment.
Jake Eberts:You know, classically, we pay for blood plasma here in The United States. You drop, dude, in, for instance, Ontario. People in Ontario drive over to the drive over to The United States and will donate in Buffalo, New York or whatever. And United States will export blood blood products to Canada. Right?
Jake Eberts:And so, like, the actual ethic like, the actual, like, functional consequence of those regulations aren't necessarily to decrease this supposed problem if it is one. But to begin with, I think it's just a really bad misunderstanding of how incentives and how these sort of things work. And so, even the trial I did, the Shigella trial was sponsored in part by Austibustur in France. I can't speak to their reasoning, but they could not have probably run the study in France just because you would need to pay people much, like, probably more than legally, they could get paid in France in that year. And so you send it to The United States.
Jake Eberts:Right? So it's like, there's yeah. I I think some institutions do better than others. Other trials I've experienced with the institutions hosting them, even when they treat auditors well, then they do, are really, really stubborn and hesitant when it comes to discussion of compensation. Even if you get, for instance, to pull a not so hypothetical example, a group of participants who are participating in a study who write a very kindly worded letter to an institution saying, we are being treated well, but we really need to talk to your IRB about compensation practices.
Jake Eberts:Because for this trial in particular, are really, really inadequate, and that's harming volunteers because people are dropping out early. And that's bad for your research in general. Having participants, you
Wilbur H. Chen, M.D.:know, hand you
Jake Eberts:an issue on a silver platter, saying here's a perennial issue in research ethics. We'd love to talk to you about it, and being rebuffed, I think, is a good example. Different institutions are willing to engage with volunteers and participants on different at different levels. And it is incumbent on the IRB to kind of take that seriously when it does happen, and but more often just be more proactive about it.
Catherine Batsford:Absolutely. Absolutely. What advice would you give an early career researcher, who wants to prioritize ethics and trust building in their work. And this isn't necessarily a human challenge study. It could be any study.
Catherine Batsford:Is there advice that you would give them?
Wilbur H. Chen, M.D.:Oh, yeah. So this is a great question because the other hat that I wear at my university is that I'm the co director of the K 12 program, which is an institutional junior faculty mentoring award where we basically are trying to develop young faculty's careers. And this is all for a research career, by the way. And so part of that development plan that we have in place is that they should understand the ethics of research on multiple different levels. So if they're performing human research, they should undergo training on human research subjects ethics.
Wilbur H. Chen, M.D.:They should understand that no matter what type of research that they perform, that they have a role and responsibility to perform research in a way that's reproducible, that data is reproducible and that it is rigorous. In other words, that the data that they generate, research data, is rigorous and made in a way that is standardized. I'll just segue. There's a problem in general with science in which people publish their research and then other people try to reproduce their research and are unable to reproduce it. And that means that for some reason, their data is not reproducible.
Wilbur H. Chen, M.D.:That's a problem. Their data, meaning that the primary person's So my approach as a scientist is that all of my research should be done in such a standardized way that if someone else were to try to do my exact research, my challenge studies and whatever else, they should be able to reproduce my data. And that shows the validity of my data, by the way, that I have data that's rigorously produced and reproducible. So that's kind of really the basic tenant of kind of of a junior faculty member is to make sure that they're always performing their science in such a way, not sloppy science, not science where they're changing their methods as they go along, that it should be well thought out before the experiment is done and that they should follow that same experimental plan throughout such that that data is going to be, you know, well done. And again, that's kind of an emphasis that I always have.
Wilbur H. Chen, M.D.:So that's going back to again, the ethical framework for our research should be approached in the same way such that it is reproducible across other sites. I always encourage people to always engage in trying to think about when they're doing their research. Are they doing it in an ethical manner? Are they doing it in, again, that way that it is rigorous and reproducible? So those are kind of my mantras.
Catherine Batsford:I think you often hear that sometimes there's pushback that once I get to the IRB, then I have to defend what I'm doing. But if you lay the found work correctly, the foundation that's there, then there's no problem moving forward.
Wilbur H. Chen, M.D.:That's right. I I feel like the IRB is my friend.
Catherine Batsford:Yes.
Wilbur H. Chen, M.D.:That they are basically verifying my methodology and my approach and my, my proposal. And if I were to ever come and try to propose something crazy, I would want the IRB to catch me and to call me out and to say, no, I don't think you should do it this way. Consider these things.
Jake Eberts:Mhmm.
Wilbur H. Chen, M.D.:So I I never feel antagonistic against my IRB. I really feel like it's a collaborative partnership in which they are able to verify what I propose.
Catherine Batsford:And I had one one one one more last question. So as far as once a study is finished, is there an a moment in which you could share the information back with the participants? Just out of curiosity, if you've done this, I'm sure you're you're wondering, did I help? Did it move it forward?
Wilbur H. Chen, M.D.:Yep. Well, we we always intend to publish it in peer reviewed scientific literature, which means that it doesn't get to the participant themselves. Oftentimes after a study is performed and we've published it, or we're about to publish it, we will either create a website to communicate it, email back our participants individually and say, hey, the study results are done. You can find it here. We also publish the results on clinicaltrials.gov, which is again, a required registry.
Wilbur H. Chen, M.D.:So that's kind of a clearinghouse, a central place to find results. If we have a really important piece of work, sometimes we have a press release that is sometimes launched with either the NIH, if there are funding partners or with the industry partner. So there are different ways for my international research. Again because I'm working in developing country settings. Oftentimes that means because and they because they have less technology for, you know, looking at websites or this or that What we often do when we're ready to publish is we go back to those communities and have a town hall in their local language presented by the local scientists, and we basically report back to them.
Wilbur H. Chen, M.D.:This is the study that you gave us permission to do in your village. This is the result. And this is the reason why we think it's important. And so we talk about the results of the study, but also talk about generally why it was important for them to engage in it and what are the important features of what we found. So again, I think that that's something that I wish we could do more in The Us, but it's so hard to do kind of those types of town halls because geographically we're more dispersed and then kind of people have less time to kind of take out of the day to attend the town hall and for us to kind of schedule multiple town halls for everyone's schedule.
Wilbur H. Chen, M.D.:But these are the kind of approaches in which we want to communicate the importance of the science that we're doing back to the participants.
Catherine Batsford:Oh, I love that. Do you think as a participant, if you knew some of the data would come back to you, would you be more interested, less interested? Would it not matter?
Jake Eberts:You mean, like, study, like, study results? Yeah. I think some are more like this is another thing where it's I'm sympathetic to, like, it like, there's a lot of paperwork involved in clinical trials. You're very busy, and some people don't care. But it is always shocking to me how little studies get back to people.
Jake Eberts:One of my former colleagues at a one day center deliberately contracted malaria as a graduate student, and that ended up being really pivotal in a trial that is now that that was a pivotal part of a pivotal human challenge study for what is now the r twenty one malaria vaccine. And that vaccine, as we speak, is being rolled out in in West Africa. It's gonna probably save a lot of lives. Yes. If he did not work for one, he probably would not know that fact.
Jake Eberts:Right? Like, he got malaria, and they didn't really follow-up. And that's, I think, a pretty egregious example where it's not hard to send an email. And it is yeah. That is something that I think is really common and I think is really, really easy to fix.
Jake Eberts:Much more so than, competition issues. Just, tell people what happens. And, like, you know, if five years down the road, your the study you were in was an important part in terms of helping a life saving vaccine, you have all our emails sitting in a binder somewhere. I understand that getting graduates soon to go out and fish those out and put them into a form is not the most exciting use of time, but like it is, I think, a pretty basic currency. And it's something that a minority of institutions do, unfortunately.
Catherine Batsford:Yeah. So if you had to tell someone how to design a research study that would pull in participants, that would make you interested, do you have an idea of what you would say?
Jake Eberts:Yeah. I don't think there's a magic bullet per se. And some of is topic specific. You know, for many people, there's logistical issues. If you're having trouble recruiting, that means, like, if your study has been approved by an RBA is ethical and you're having trouble recruiting, then you should really just consider raising the payments.
Jake Eberts:Like, that off the bat should be a good idea and something you should consider. And the IRB, you should be willing to entertain. And so, yeah, a lot of it is fairly, I think, pretty straightforward. Like, treat people nicely and respectfully, communicate clearly. I will say one of the things that is really interesting is the degree which, like, often, again, private firms are pretty good about like giving us like, here's, you know, three d tour of the facilities.
Jake Eberts:Whereas other institutions are really not quite as upfront about what, you know, is going to be involved. And this is something that's always really interesting to me, like the day to day, like, my my, you know, my ability to consent is is affected as or my willingness to consent is affected by, like, the the baseline conditions that I'm going to be living in. Right? If I'm living in if you put me in a small dark chamber in the back of the room and I can't leave all day and it's, you know, cold or wet, I'm gonna not consent to that. And, you know, if the Wi Fi doesn't work and I have to work remotely or I like you know, the last place I wanna be cut off from the world and my family, right, is, you know, in a you know, a quarantine medical research facility where I'm getting dysentery with a lot of the Right?
Jake Eberts:So, like, baseline things like that, that's not necessarily the job go and inspect. But lots of kind of like quality of life things and comfort things go a long way. And that's like stuff that shows up in like, there are zines dating back to the nineties, one called Guinea pig zero about so called professional medical research participants or the professional Guinea pig. Right? And and who who, like, would do reviews at places and say, like, the staff here are really nice.
Jake Eberts:The staff here suck. These people's blood drawers suck and, like, always take tries and that hurts. Like, like, those baselines are quality of life things that I think are pretty intuitive, can go a long way and just make people feel valued and respected and more willing to to come in for the next appointment.
Catherine Batsford:Dan, you had a few more questions?
Dan McLean:I was curious. Did you ever meet any of the other participants and have a chance to connect with them about their experience?
Jake Eberts:Yeah. So the Shangela study was like we all do, but we were all in the same way. Some studies, particularly respiratory virus studies will involve like individual quarantine. You don't want people cross infecting each other. Respiratory viruses are obviously much more infectious.
Jake Eberts:And so you just want to keep people kind of contained. But for the Chanel one, we were, you know, we were in the, our little kind of curtain pull around hospital bed sort of situation and friends with several.
Dan McLean:And I guess my last question for you, and then I'll hand it off to Catherine is do you have any other plans to participate in another trial anytime soon?
Jake Eberts:Yeah. So right now we are still in the phase where every single NIH study has been frozen, the peers, which is incredibly concerning, but, it's being personally here. But I think that I kind of joke with friends that once I, know, I I should get, like, punch card. And once, like, my third disease, I get, like, a fourth one free or something. The kind of for me, a lot of it is, like, I am, you know, I'm relatively young.
Jake Eberts:I'm blessed with, you know, physical health, and I don't have to worry about, you know, I I it's something that feels good to kind of, like, give back. So the short answer is yes. I would love to. Like I said, I live in DC, so there's just a cornucopia of idiotic and fun diseases you can get for the greater good here. A lot of it's just a question of logistics and trying to sign up and get in at the right time.
Catherine Batsford:Well, as another member of the public, thank you. Thank you for doing it.
Jake Eberts:Like I said, I was not doing it purely Mother Teresa's end. I got to know, but you're then welcome.
Catherine Batsford:That's okay. That's okay. The end result, it was great. So thank you. And thank you for coming on the podcast.
Catherine Batsford:This was fascinating.
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