Taboo Trades
Taboo Trades
Clinical Research Ethics with Holly Fernandez Lynch
Holly Fernandez Lynch and I discuss clinical research ethics, including challenge trials, research subject payment, and diversity in medical research with co-hosts Rahima Ghafoori and Caroline Gozigian (UVA Law '23). In this episode, Holly introduces the basic regulatory framework governing clinical trials, with a focus on laws and rules impacting payment. She also discusses the benefits of and concerns about human challenge studies, and shares some historical examples. In the next episode, Part II of our interview, we explore issues of coercion, inducement, and exploitation more explicitly.
Holly Fernandez Lynch, JD, MBE, is Assistant Professor of Medical Ethics in the Department of Medical Ethics and Health Policy at the Perelman School of Medicine (PSOM), University of Pennsylvania. She co-chairs the PSOM Research Ethics and Policy Series (REPS) and serves as Assistant Faculty Director of Online Educational Initiatives in the Department, where she helps lead the Master of Health Care Innovation. She has a secondary appointment as an Assistant Professor of Law at the University of Pennsylvania Carey Law School.
A lawyer and bioethicist by training, Professor Fernandez Lynch’s scholarly work focuses on Food and Drug Administration (FDA) pharmaceutical policy, access to investigational medicines outside clinical trials, clinical research ethics, and the ethics of gatekeeping in health care. Her specific areas of expertise include Institutional Review Board (IRB) quality, payment to research participants, research prioritization, pre-approval access pathways (e.g., Expanded Access, Emergency Use Authorization, and Right to Try), and efforts to balance speed and certainty in drug approvals, including pathways that rely on post-approval trials such as accelerated approval.
Links:
Lynch HF, Darton TC, Levy J, McCormick F, Ogbogu U, Payne RO, Roth AE, Shah AJ, Smiley T, Largent EA. Promoting Ethical Payment in Human Infection Challenge Studies. Am J Bioeth. 2021 Mar;21(3):11-31. doi: 10.1080/15265161.2020.1854368. Epub 2021 Feb 4. PubMed PMID: 33541252.
Shah SK, Miller FG, Darton TC, Duenas D, Emerson C, Lynch HF, Jamrozik E, Jecker NS, Kamuya D, Kapulu M, Kimmelman J, MacKay D, Memoli MJ, Murphy SC, Palacios R, Richie TL, Roestenberg M, Saxena A, Saylor K, Selgelid MJ, Vaswani V, Rid A. Ethics of controlled human infection to address COVID-19. Science. 2020 May 22;368(6493):832-834. doi: 10.1126/science.abc1076. Epub 2020 May 7. PubMed PMID: 32381590.
Largent EA, Heffernan KG, Joffe S, Lynch HF. Paying Clinical Trial Participants: Legal Risks and Mitigation Strategies. J Clin Oncol. 2020 Feb 20;38(6):532-537. doi: 10.1200/JCO.19.00250. Epub 2019 Jun 14. PubMed PMID: 31199697.
Another historical example of a challenge study happened in Guatemala after World War II. So the researchers who were involved in the study of syphilis in rural Alabama, well known as the Tuskegee syphilis study, also were doing research in Guatemala, but they went to Guatemala with the intention of studying prophylaxis against various STDs. And they went to Guatemala because at the time, people who were in prison were allowed to have visits with sex workers. And those sex workers were licensed and regulated by the government. And so they could control the sexual relations that were happening and they could see who was being exposed to these different diseases. So they thought, well, isn't this convenient, right? We can control who's having sex with whom and we'll know who's infected. But it turns out that it is, hard to get prisoners to cooperate, and it is harder to transmit these STIs than one would have thought. So they got rid of that approach. They ended up manually inoculating prisoners and other vulnerable populations with these pathogens so that they could eventually move into studying prophylaxis. Extraordinarily shoddy science. It was kept secret for decades. It was uncovered by a historian of the Tuskegee syphilis study who was going through one of the researcher's files and said, oh my God. Hey, hey, everybody.
SPEAKER_08:Welcome to the Taboo Trades podcast, a show about stuff we aren't supposed to sell, but do anyway. I'm your host, Kim Kravick. In today's episode, the Taboo Trades Gang discusses clinical research ethics with Holly Fernandez Lynch, including challenge trials, research subject payment, and diversity in medical research. It's a great conversation in which I learned a lot and hope that you will too. In this episode, Holly introduces the basic regulatory framework governing clinical trials with a focus on laws and rules impacting payment. Thank you so much for joining us. Policy Series and serves as Assistant Faculty Director of Online Educational Initiatives in the department where she helps lead the Master of Health Care Innovation. She has a secondary appointment as an Assistant Professor of Law at the University of Pennsylvania Carey Law School. A lawyer and bioethicist by training, Professor Fernandez-Lynch's scholarly work focuses on food and drug administration pharmaceutical policy, access to investigational medicines outside clinical trials, clinical research ethics, and the ethics of gatekeeping in healthcare. Her specific areas of expertise include institutional review board quality, payment to research participants, research prioritization, pre-approval access pathways, for example expanded access, emergency use authorization, and right to try, and efforts to balance speed and certainty in drug approvals, including pathways that rely on post-approval trials, such as accelerated approval. I'm here with my co-host for today, Rahima and Caroline, in advance of our upcoming discussion with Holly Fernandez-Lynch. So guys, first introduce yourselves and say hello to our listeners.
SPEAKER_00:Hi, everyone. My name is Caroline Gosgan. I am a 3L here at the law school, and I went to Cornell University for undergrad. I'm from Cooperstown, New York, which is a small town right in the middle of New York State.
SPEAKER_02:And I am Rahima Ghaffouri, and I'm a 3L here at the law school.
SPEAKER_08:Now, you both specifically requested to be hosts for this episode. What was it about the topic that made you interested in this?
SPEAKER_00:So when you were describing some of Holly's research areas— and what her educational background is, it made me think of one of my friends from growing up, who is actually doing a joint JD and PhD in healthcare ethics. So it's kind of a similar type background to Holly. And I know that going forward in the discussion with her, we have some classmates that are interested in hearing about how Holly kind of landed in that research area and how she kind of fell into the background, the educational background that she did. So when you were talking about Holly, it made me think of my friend. And I hadn't really thought too much about this intersection of bioethics and law before. But the program that my friend's doing sounds really interesting. And so I thought that this would be a cool topic to be a co-host for. And I know specifically the reading we had done of Holly's was pertaining to human infection challenge studies. And I had actually never heard of the official term before I knew kind of generally what the concept was, but I found the reading really interesting and I'm super excited to talk to Holly today.
SPEAKER_08:Yeah, I'm really interested as well. And you know, it's funny, I'm not sure I knew she was a lawyer when... I mean, I definitely didn't know at first. I just knew she was a bioethicist and she did all this, probably published more articles than anybody on the ethical compensation of human research subjects. And I don't think I realized she... I definitely didn't realize... initially. I'm not sure if I knew she was a lawyer until after I had already invited her, or maybe when I looked her up to find her email or something. I was like, oh, she's a lawyer. I actually didn't know that. So I'm also interested in hearing a little bit about her background and how she developed this interest and that type of thing, as I know others are as well. Rahima, what about you?
SPEAKER_02:Yeah, I think I'm just excited to learn more about the clinical trial process in general. I don't think I know anybody in my personal life that has actually participated in one. I And so it's a totally new area for me. And I think also another really interesting example of the potential corruptive effect of money and yet another realm that maybe most people aren't thinking about. And then, of course, there's a conversation to be had about, you know, the notions of coercion, which has always been a fun word for us here on Taboo Trades versus inducement. And then also the stakes feel high when it comes to something like medicine. And so something that has tremendous societal value and it'll be really interesting to learn and hear about how we think about money when it comes to something like this. Can we put a price tag on this? Should this be something people do for the sake of science for altruistic reasons? And the answer seems to be yes to all the above and we can attach an amount to it. And so if that's the case, then the million dollar question is, You know, how much is that?
SPEAKER_08:Yeah, this is one of the things that I really like about Holly's research as well, which is that I feel like she's very practical about it, about the competing interests, which she lays out very carefully in the papers that we're going to talk about today, but also the recognition that Often in the absence of compensation, you're undersubscribed and you may be inadvertently perhaps targeting particular populations if the amounts offered are too low to be attractive to people from other socioeconomic groups. And so I feel like I'm convinced it's because she's a lawyer that she brings this practical strain to her analysis. Okay, so what is it that you guys are hoping to get out of our discussion with Holly today? In addition to the things you've mentioned, what is it that you are hoping to learn from her. Caroline, why don't you start us off?
SPEAKER_00:Sure. So I'm excited to hear questions from all of our classmates because we have a wide range of what's going to be talked about and asked of Holly today. So I'm interested in learning more generally about the clinical trial process, but more specifically, I'm also really interested in kind of hearing about the payment considerations that go into these human challenge trials. And she narrowed down some specific factors that are specific to human challenge trials rather than clinical trials. trials more generally. So I'm interested in kind of hearing how she landed on those factors. And then another thing that goes into this payment consideration that I'm really interested to hear about is learning about the breakdown of different payments for clinical trials that she describes. So she describes three kind of general categories, including reimbursement, compensation and incentives. And I'm sure we'll get into a deeper conversation about this when we're recording with Holly, but I'm really interested to hear how these different forms of payment actually shake out in practice. So to me, when I was reading her articles, compensation and incentive categories seemed like they could, in practice, blur together a little bit, specifically from the perspective of the participants. I could see how perhaps from the perspective of research developers and who are in charge of these trials and kind of assigning the payment and whatnot how in their minds it could be compensation incentive categories could be more distinct but when i'm thinking from the participant standpoint i'm seeing how those could be easily blurred so that's something i'm super excited to talk to her about and see if she can kind of shed light on how those categories play out more
SPEAKER_08:that is a great point caroline and i I especially appreciate your emphasis on does this depend on whose perspective we're looking at it from, right? from the perspective of a researcher, especially when they're trying to line it up with particular goals, right? Whether it's fairness, justness, or ensuring a sufficient enrollment. And so I can see that at the same time from the perspective of a research participant, especially since compensation doesn't vary by income, which I agree with them, it really shouldn't, right? There's a uniform payment metric, not one that varies depending on whether you're a barista or a lawyer. But what that means is that what counts as compensation for one One person might actually be an incentive for another. And so it might make a difference sort of whose perspective we think we're taking here. And I think your point's a really good one. Rahima, what about you? What are you hoping to get out of today's discussion?
SPEAKER_02:Yeah, like I said, I just would like to learn more about the clinical trial process in general. But I think my questions reflect more specifically of a curiosity about ethical consumption across different socioeconomic backgrounds. And so questions like, do we over-select low-income populations? Do we maybe subconsciously avoid people who don't have a car or rent their home rather than own because that might be an indicator of wealth? And then I'm also curious to hear the case for fixed rates, like you mentioned, rather than proportional pay. And also just curious about the optics of it. What do we think when there's a higher amount being offered for one study versus a lower amount being offered for another? And I just, yeah, I just want to hear Holly's thought process on all of this and really just the method behind coming up with a number because there's just so much to talk about and so much to learn.
SPEAKER_08:Yeah, these are really good points. I especially like your point, Rahima, about, I mean, we focus a lot on recruitment and the role of payment in recruitment and what effect that can have. And there's focus as well, of course, on I think the actual document, right? You know, what the recruitment document contains. I would be interested to hear from her how they think about and whether all researchers think about some of the other issues that you just raised, such as are we recruiting in a way that is going to exclude inadvertently people who, for example, don't have a home or don't have a car or whatever it is, right? People who are public transportation people versus commuters. I mean, does thought go into the way in which we advertise for or recruit or whatever subjects that attracts a particular group or makes sure that it reaches everyone? And then is the study itself structured in such a way that, for example, people who can only take public transportation aren't burdened more than people who have a car and can drive to the facility or whatever it is. So yeah, I would be, or vice versa, right? So I would be interested in hearing all of those. Caroline, anything else from you that you're hoping to talk to Holly about?
SPEAKER_00:Yeah, my last kind of larger question relates to something she mentioned in one of her articles that we read. So she discussed how there's a lack of pay transparency in human infection challenge studies, and that can obviously pose a variety of issues such as, you know, Does that mean it's harder to have consistency among these types of trials? It also makes it harder for Epic Review Board members, as well as someone like Holly, to be able to kind of analyze these payment structures. Obviously, pay transparency is certainly not an issue that's only exclusive to clinical trials. It happens across the board in so many different areas and industries. But I was wondering if Holly had any thoughts about how to increase transparency transparency that are specific to clinical trials and also specific to the area of human challenge study. So I'm just interested to hear if she has any specific thoughts on that.
SPEAKER_08:Yeah, these are great questions. I'm also interested in the lack of transparency issue and whether that's sort of what's causing it. Is it just a lack of attention to it? Is it that we need some more centralized mechanism? Or does it just need, does it need more attention? Sort of what are the reasons? And one of the was it's not that there are no special considerations for challenge studies. There are. But that it doesn't require a complete rethinking of the basic compensation and ethical framework for clinical studies. And I found that to be quite interesting because I think a lot of people approach it as if it's this completely radically different thing. And of course, it is different. And we'll talk about the ways in which it's different during our discussion with her. But it's not different in a way that requires a complete abandonment of the ethical framework that we already have. And has been proven to be useful. Great. So let's go
SPEAKER_05:talk to Holly and our colleagues.
SPEAKER_08:And they also recorded a short little roundtable with me just earlier this morning about the types of questions that we had for you and what we were hoping to get out of the discussion. So that's who they are. As I said, the students were really interested in learning a little bit more about your background and especially how you sort of first became interested in the bioethics and law combination. I believe a lot of our listeners will be interested to hear that. I'm going to turn to Ryder to start us off with that.
SPEAKER_11:Great. Thank you so much. Thank you so much for coming. So my question is going to describe, when I think of health and law, my mind immediately goes to malpractice and pharmaceutical companies. But the majority of your research focuses on research ethics. And I'm curious, did you go to law school knowing you would pursue both law and bioethics during your time at Penn? I feel like this is kind of an uncommon dual degree, at least compared to a JD, MBA. And also, when you decided to study bioethics, did you go into it knowing you wanted to focus on research ethics, or was this specialization developed throughout your career?
SPEAKER_05:Yeah, great question. So, you know, certainly bioethics master's programs are... more unusual than MBAs or other degrees that you can do at the same time as a JD. Although at Penn, where I trained and where I am now, lots of folks do the MBE program with the JD. It's one of the more popular dual degree programs. So I got interested in bioethics during my undergrad. And I just happened to be in an intro to biomedical ethics course as a freshman. It's not something I had ever heard of. You know, this is like the late 90s. But there were lots of ethical issues happening. So for example, I don't know if this still happens, but at the time, it was very common in our university newspaper for there to be ads asking or, you know, offering to pay quite a bit of money for Ivy League egg donors. So, you know, it was kind of in the ether at the time. There was a lot of concern about cloning and that type of thing, emerging interest in genetics and ethics. And so I got really interested in it as an undergraduate. But one of the things to know about bioethics is that nobody is just a bioethicist. I don't mean that in a derogatory way. I mean, bioethics is such an interdisciplinary field that everyone brings their own disciplinary hook to it. So we have philosophers and sociologists, anthropologists, all sorts of different types of people and doctors and lawyers, of course. And so I was kind of thinking, well, what's my hook into bioethics going to be? I was very interested in policy. And so I thought I should go to law school. And that will be my inroads to bioethics and my inroads to having an influence on the policy side of things. When I was in college and law school, I did no research ethics work whatsoever. There was a research ethics course that was offered in my program, but I didn't take it. I was really interested in reproductive technologies and reproductive ethics. But when I graduated, I knew I wanted to work in private practice for a short period of time. I didn't stay there for long. I treated it as my residency, the way physicians have their residency. I wanted to actually practice law, see what it was like, you know, extent as, as an extension of my training. So I went to, um, a big DC law firm at the time it was called Hogan and Hartson, and it's now called Hogan levels, and they have a leading FDA practice. And I thought, well, where am I going to be able to practice traditional law, but also with a bioethics spin. And it was in the context of, um, you know, FDA law where I now spend a lot of, of my time and attention. Um, And so that's really how I got interested in research ethics, because I was working for these companies who were trying to get their products approved by FDA and were trying to generate the evidence that was necessary for approval. And so that led to other forays into research ethics. I went on to work at the Division of AIDS for a period of time as a literal card-carrying bioethicist, which was something my parents thought wouldn't exist when I was studying in this field. So in any event, a lot of it was serendipity combined with interest.
SPEAKER_08:That's great. So now I see completely why you describe yourself first as a bioethicist. I mean, you were first a bioethicist and then pursued law in order to further your interest in bioethics rather than the other way around, rather than coming to law school, becoming interested in bioethics and approaching it from that way. We were first going to start out with some questions about clinical trials generally and the oversight process. Speaking for myself, at least sometimes the students have depths of knowledge that I'm unaware of, but this is not an area I know a lot about. And so I think the background would be helpful. I suspect there are listeners to the podcast who don't have that background knowledge as well. So I'm going to start with Rahima.
SPEAKER_02:Hi, Holly. Yeah, I'm one of those people who also doesn't have a lot of background knowledge on this. So I was wondering if you could talk a little bit about the current recruiting processes for clinical trials and how individuals across all socioeconomic backgrounds are being made aware of them. Because you mentioned that there is an unjust inducement concern that comes with offers of payment and their disproportionate appeal to worse off populations. But they also might be the only way sometimes that recruitment goals are met. And so how do these incentives impact the overall recruiting process and the potential selection bias that may arise as a result? And something that kind of prompted this question for me was that I went and got a flu shot and then I got an email from CVS being like, do you want to participate? in this trial. I didn't even look at it. I just deleted it. But it got me thinking, how do we reach people who don't have access to this type of information through email? And how are they reached? And do recruitment tactics change when you encounter different populations? And then do we maybe inadvertently avoid people who don't have a car or rent their home versus owning it or are completely unhoused? And because that might be an indicator of wealth. And I know that was like$10 questions in one, but feel free to tackle any of those.
SPEAKER_05:This is a great set of questions. And I want to set payment aside for a moment and just talk about the recruitment process and how it goes. Although before I set payment aside, I will talk briefly about this idea of unjust inducement. And that's the idea that payment could be most attractive... unsurprisingly, to people most in need of money. And so then the concern is that you might be concentrating the burdens and risks of research participation on certain demographic groups unfairly. The very little bit of empirical evidence that exists about this question of unjust inducement suggests that payment is actually not panning out that way such that you're having a higher representation of disadvantaged populations in some of this research. So let's set the payment questions aside for a second and also recognize that there are lots of different types of research for which people might be recruited. So for example, when I lived in Boston, we used to take my son to MIT's baby lab and they would do like, they would do psych experiments with him. And he thought it was a great time and he'd walk away with a little toy or a little book or something. And I felt good about supporting research in some way, given my work in this field. And that was something that his pediatrician, I think, had a flyer up in her office. And I said, oh, this would be a nice thing for him to do. And wouldn't that be fun? That is not how things typically go for pharmaceutical company-sponsored clinical trials. Think about this from a pharma company's perspective. You want to get your trials done as quickly as you possibly can, because you need those data to prove to FDA that your product is safe and effective or its intended use. So you start with your phase one studies, which are typically very small studies of healthy individuals to get a basic sense of whether this product is safe to use in people, maybe get a sense of dosing that you want to try in the next stage of your study. Then you move on to phase two studies. That's when you start to actually enroll people with the disease or condition of interest. Maybe you have a couple of hundred people in that type of study. Often, you know, these will be multi-site trials because you're trying to, you know, get people as quickly as you can. And you can do that more, you know, can do that rapidly the more sites you have involved. Phase two, you're testing safety and effectiveness. If things look good at that stage, then you might start enrolling a couple thousand patients in your phase three studies. And that's where you're really trying to get a handle on effectiveness, right? So pharma wants to get these done as quickly as possible. And they do that in a number of ways. They build relationships with investigators at academic medical centers, for example, who can serve as site leads to recruit their own patients into the clinical study. They work with contract research organizations, which are businesses that run, you know, run trials and have entire arms of their companies that are devoted to recruitment. But to get down to a little in a Thank you. do a study about, you know, a new communications method about cancer screening in affected populations. I might have some people from affected communities participate as co-investigators with me or have, you know, a community advisory board that can help introduce me and my work to the community, help make my research as as relevant to that community as it possibly can be, can help build trust that I am a researcher that the community ought to be willing to engage with because I'm not going to be exploitative. You know, so there are, it's a lot about relationship building. It's a lot about building awareness that there are these studies going on. And then payment comes in, you know, as one piece of the puzzle, right? To, you know, so there might be barriers for people who say, oh, that's a really interesting study. Let's go back, you know, the baby lab study that I was talking about. My son was able to do that because my husband was a stay-at-home dad, right? If I had had to take him to all of those appointments, it wasn't going to happen. I had a nine-to-five. And so... thinking about what are the barriers and how can we resolve those barriers, that's not just about payment. That's about transportation. That's about having your study visits available for booking appointments at night and on the weekends when people who have a job are going to be able to participate. It's about not making people always come into the academic medical center, but rather going to where they are. It's about having remote clinical trials which is something that COVID helped us understand was possible to do. And so the payment stuff comes in as you know, I don't want to suggest it's a cherry on top because I don't think that's true. It's something that's really critical to successful recruitment in many instances, but it's just one piece of what you need to do for successful recruitment.
SPEAKER_08:Thank you. So related to that, Marley had some questions specifically about building trust in diverse communities, and you've already alluded to some of the devices that you use. Marley, do you want to follow up on that?
SPEAKER_01:I just was wondering, you definitely addressed it, but I was going to pivot. Do you have like an anecdote that you could share about, um, some research or like a way that you were able to reach out and build that relationship that we could like hear about?
SPEAKER_05:Sure. So I don't do clinical trials myself, but let me give you an example that maybe some of you have heard about. In the context of studying COVID vaccines, it was really important to make sure that we had diverse recruitment and diverse enrollment across a broad variety of demographic groups. One, to make sure that there weren't going to be differences across demographic groups about how the vaccines work and whether they were safe, but also to build trust in vaccines, in the COVID vaccines. And there was a great New York Times article that was talking about how one of the companies involved in developing the vaccines actually paused recruitment because they were not seeing the diversity that they wanted. And so they kind of went back, redoubled their efforts in more marginalized communities to make sure that they were going to be recruited. And literally what they did was hire members of the community to go door to door, right? And I mean, literally go door to door in these communities where they were hoping to recruit from and say, is this something you might consider? What might you be worried about? I'm participating. Here's what it's been like. You want to talk to other people who have participated. Here's why it's so important to have diverse enrollment in these studies. One of the really revealing things about this New York Times story was just recognizing all of the barriers that people face to clinical trial participation. So, for example, there had been... There had been a shooting in the neighborhood. And so as the reporter was there, they were having a memorial service for a child who had been killed in this shooting. And there was somebody who they came across who was food insecure. So there's lots of reasons why people don't have clinical trial participation at the very top of their mind. And so This has been a very longstanding problem is the lack of diverse enrollment in clinical trials because sponsors have been willing to just kind of take the first comers, right? Take who is available. And there's a privilege to being able to easily participate in clinical trials. So it can slow recruitment down to go after diverse populations. It can be more expensive to go after diverse populations, but it's nonetheless critical. And I think we're really at a pivotal moment where sponsors and others, regulators, for example, are emphasizing how important it is to take those steps, even if it takes a little bit longer.
SPEAKER_08:We are going to return to this theme and question of how you build trust, both in diverse populations and more generally, Holly, which of course has been very much on everybody's minds in recent years. And we do have some more questions about that coming up. For now, Mary and Brian both had questions about the legal risk paper and enforcement actions. I think that in order to avoid having you repeat yourself, we might have Mary ask her question, then Brian, and then you can probably answer them both together. So Mary, why don't you start?
SPEAKER_04:Hi, Holly. Thank you so much for joining us. Yeah, so my question is, after reading that paper on legal risks and mitigation strategies, where you discuss the legal risks of participant remuneration and discuss the federal anti-kickback statute in particular, just how likely is enforcement action if researchers to not take the steps to mitigate legal risk that you recommend in the article. Brian?
SPEAKER_10:And similar, how prevalent are enforcement actions taken against participants of clinical trials and what factors were used in an agency's decision to bring an enforcement action?
SPEAKER_05:Yeah, thank you for those questions. So let me start off with yours, Brian. I am not aware of any enforcement action against a participant. Right. So we're thinking about anti kickback. The enforcement would be against the entity that's offering the inducement. Right. Now, there's a couple of different legal concerns that might come up around paying research participants that have not gotten that much attention, because often when people worry about paying research participants, they worry about things like undue inducement and coercion. And we can talk about those in a bit. Holly, I
SPEAKER_08:actually was completely unaware of these legal risks until I read your paper. So, I mean, not that I'm an expert here, but I mean, I'm just saying I have that's how little I have seen talk of the legal risks.
SPEAKER_05:It's really not something that gets very much attention. And frankly, we struggled a little bit in writing the piece because we worried that there has not been enforcement action that we're aware of. And we don't want to make a big fuss over something that's not actually a major legal risk. On the other hand, we knew anecdotally that sometimes investigators hear from their institutions that they have to be careful about these issues. And there's a kind of conservative approach. Whenever you mention anti-kickback, The penalties can be really severe, right? So it's a felony offense. There can be civil monetary penalties. You can be excluded from participating in federal programs. So if they were to drop the hammer on you, it would be a huge hammer. And so sometimes we've heard that people get worried about those things. So anti-kickback is one angle. The other on the participant side, Brian, is... If you are receiving money for your participation in research and the amount exceeds more than$600 annually, the entity that's paying you is obligated to report that to the IRS. So participants may not realize that they actually owe It's income, right? They actually owe tax on those payments. So that exposes them to some risk if they don't recognize they need to pay. The other way it exposes participants to risk is if the institution insists that they have to have their social security number or whatever it is for their tax forms. There's lots of research that you might want to enroll undocumented people in or people who have other privacy concerns or something and don't want to be tracked in that way. There are workarounds for that. The other thing to keep in mind for participants is that they might be... getting government benefits that are income dependent. And so it's important for them to be aware that if they are getting these payments, that could be getting these research payments that could count against their income levels for their eligibility for some of these government benefits programs, which is something that, you know, I've not seen spelled out in informed consent forms. Right. And so you'd really hate to pay people a fair amount for their participation, but then have them lose access to some critical financial benefit. So those aren't I mean, the IRS issue is an enforcement issue, but the loss of government benefits is just something to make sure that people are aware of when they're deciding whether or not to participate and accept payment. On the anti-kickback statute issue, is a pretty broad legal prohibition, right? So what anti-kickback statutes prevent at the federal and state level is knowingly or willingly offering remuneration with the intent to induce the use of services that are paid for by federal healthcare programs. So the way that this could play out in a research setting is that you offer to cover people's co-pays for expenses that they might incur as a research participant. And you think that's great. That's overcoming some fine barrier to participation. It might even be an incentive to participate. But oh no, now we are inducing people to come to our health center and then we are going to ask Medicare to pay for the rest of their bill, right? So you are in fact offering remuneration to induce people to use services at your site, right? So that is a legal risk of kickback. And we know that the regulators are worried about this because there has been some discussion of giving a safe harbor for clinical research payments, but they have not adopted that safe harbor yet. So you have to think about this when you're representing clients, right? You have to say to them, well, this is what the law says. Technically, this falls within the realm of the legal prohibition. But there haven't been enforcement actions. It's probably not that great of a risk. And by the way, it's really important to offer these payments in order to get our study done, right? So what we did was we went back and looked at, you can get advisory opinions from the Office of the Inspector General. And they have, every time one of these advisory opinions has been requested about a clinical research payment, they've said, yes, it's okay. And the standards that they've used have been Does the payment accommodate the needs of the study and advance scientific validity of the study? Is it critical for people to enroll to get these payments? It's a bonus if you have a government-sanctioned or government-sponsored study, because that's another sign that this is good scientific work. And then conditions that limit the risk of overusing the federal health care program. So you're not just charging things left and right to Medicare and Medicaid, but you have regimented study protocol that says these are the services that are going to be offered as part of the trial or are critical to the science of the trial and those are the things that are going to be billed for. So there are ways to mitigate these risks, but they are in fact risks.
SPEAKER_08:Thank you. So we had a couple of questions, starting with Jen and Bridget, and then with a follow-up from Brian, about the various layers of oversight, including review boards and just sort of how it all works. How the whole package works together. I think, again, maybe Jen and Bridget should ask their questions and then have Holly respond so that we're so that she's not having to repeat herself. So, Jen, why don't we start with you?
SPEAKER_03:Yeah. Hi. So the article notes that it's advisable for to rely on ethics review boards to evaluate challenge trials. But how are ethics review boards governed if they are at all? And are the types of considerations they use to evaluate the risks and burdens of the trials similar to the ones that are noted? did in the article.
SPEAKER_07:Going off of Jen's question, I was wondering like how the independent ethical approval works if the review is both before and after the trials and then sort of what the procedure is if an ethically approved trial is later found to have violated some standard.
SPEAKER_05:Okay, great. So in the we talked about two different types of ethical review, one of which is required by law, and the other is an add-on for studies that have very contingent or kind of debatable social value as well as uncertain risks that they might pose. So the first one that is legally required is institutional review board approval, IRB approval, you might've heard of this, It's not specific to challenge studies. It's specific to, depending on where your funding is coming from or what products you're studying, it's specific to federally funded research or research products that are regulated by FDA. So Let's take a project that is doing research with human subjects. And, you know, it might be a little sensitive around the word subjects, but that's the regulatory language. Research with human subjects that is funded by the federal government or most parts of the federal government is governed by something called the common rule. And it's common because it's shared across multiple agencies that might fund or conduct research with human subjects. NIH is the biggest, but, you know, Department of Defense, Department of Energy, Department of Education, there's lots of federal agencies that fund research. They share this set of regulations that require IRB oversight of research with human subjects. And they govern the composition of IRBs. They talk about the types of members that they should have, some that are not affiliated with the institution, some that have scientific expertise, some that are non-scientific members of the board. And the things that IRBs are by regulation required to ask about research before they approve it are things like whether the risks and benefits are reasonably balanced, whether the risks of the research are minimized, whether there are appropriate privacy and confidentiality protections, whether informed consent is reasonable. And then there are also in the regulations a bunch of elements for adequate informed consent, disclosures that have to be made to the research participants. There are some exceptions to this, not often for clinical research, clinical trials, but sometimes the kind of work that I do, qualitative research, I'm often interviewing regulators or doctors. That research can be exempt as very minimal risk, not exposing people to risk of harm in contrast to a clinical trial. FDA has similar requirements for clinical investigations of drugs, biologics, devices. Okay, so that's the kind of research that's, or excuse me, that's the kind of oversight that's happening of research. This other kind of body that we talk about in the paper is, is not required by law. It's not required at all. It's just a bunch of us academics who say, you know, there might be some gaps in IRB ability to oversee really controversial research. So what would happen with an IRB is that the sponsor and the investigator would put together a protocol and you would submit that to the IRB. Now, if I'm a researcher at Penn, I submit to my IRB, but if I'm in a multi-site clinical trial that's sponsored by a pharmaceutical company, it's very likely that we're going to be using a commercial IRB, which are for-profit standalone entities that review research according to these regulations. And so we submit it to the IRB, they review, they might meet on a weekly basis, they vote on it, they send us our approval letter, or they ask us questions and ask us to make revisions. But they take my word for it, the investigator's word for it. By that, I mean it's the investigator and sponsor's responsibility to say, here's the background. Here's why this study is important. Here's what we expect the risks and the benefits to be. Here's what we're going to do for informed consent. When it comes to something like a SARS-CoV-2 challenge study, That actually requires quite a bit of outside work to figure out whether that is a reasonable and ethically appropriate study to do. And so we worried that if you were asking IRBs to evaluate those studies and they were just going on the basis of one investigator or one group of investigators proposal about social value, they might not be getting the full picture. And I don't mean that in a... you know, intentionally pulling the wool over someone's eyes, not sharing all the appropriate information, but it just actually requires a ton of background knowledge, expertise, research, discussion with experts to really drill down and say, what do we need these SARS-CoV-2 challenge studies for anyway? What's the actual social value of them going to be? Are they too risky to healthy volunteers? So we proposed an additional layer of review. I was actually involved in an additional layer of review for... proposed Zika virus challenge studies during the height of the Zika epidemic several years ago, right? And so this was a group of experts that was brought together by NIAID, the National Institute of Allergy and Infectious Diseases, which was considering funding a Zika virus challenge study. They came to this expert group and said, like, should we do it? Should we fund this? And at that time, we ultimately recommended no, that they not proceed with a Zika virus challenge study because it was not clear that the social value of it was going to be there. So I think the only part of the question I haven't answered yet is what's the oversight of IRBs or these review committees. They are regulated by the federal government, right? So FDA might audit them. OHRP, which is the Office of Human Research Protections in the Department of Health and Human Services, has oversight of over IRB. So they need to be registered with the government and they have to have various policies and procedures in place to make sure that they're meeting regulatory compliance standards. But it's really important to recognize that it's not just about regulatory compliance. The regulations say nothing about payment, nothing, not one word. They talk about informed consent. They talk about avoiding coercion and undue inducement. But it is up to the discretion of the IRBs to evaluate the ethics of payment and the ethics of a variety of other angles that come up in research settings. Did I cover everything?
SPEAKER_08:Yeah, you did. Holly, can I just ask you a couple of follow-ups? So is the proposal limited to challenge trials or are there other types of clinical trials that might meet this type of criteria of needing more external evaluation of, say, the risks and benefits?
SPEAKER_05:Yeah, so in our group's proposal, right, we were focused on not all challenge trials, but challenge trials of emerging infectious diseases where we don't yet have a cure available. Got it, got it. But another example might be a xenotransplant study, right? So you probably have seen the news about the pig heart transplant, right? That is for search. And that is really... you know, controversial beyond what an IRB would normally see in its day-to-day work requires a lot of additional expertise. So that might be another example.
SPEAKER_08:Okay. And so then the other question I had was going to be whether this was still just a proposal or whether there had actually been adoption of it, given that you said you, you sat on another layer of review for Zika, there must've been at least some uptake. Is that right?
SPEAKER_05:Yeah, well, so it's interesting. A lot of my work related to challenge studies and this proposal for, you know, an extra layer of oversight came from that work that I did in, I guess it was 20, it must have been 2016 or 2017. And so we started thinking about, oh, the ethics of challenge studies and emerging infectious diseases. And then Zika, you know, kind of petered out. And then all of a sudden COVID happened and there was more conversation about challenge studies than I had ever expected to happen. Now, the engagement that I had through that NIAID committee was actually before an IRB would have even looked at it. But we were kind of agnostic about whether it would have to come before or after IRB approval. We just kind of recognized that IRBs in many instances are generalist bodies. There might be the Penn has an IRB that focuses on the oncology studies, right? So there's some specialization, but when you really need to drill down and do additional research to figure out whether the study is ethical, that's where we were thinking. So it's, yeah, I mean, a bit of uptake, but I don't think... Because it's added burden, requires added resources and delay... it's got several strikes against it. There's so much attention to like, you don't get in the way of the science. And that's something that we ethicists are always saying, like science has to be ethical and that takes time and you can't rush everything, you know? So a bit of tension there.
SPEAKER_08:Okay, great. Thank you for that. We have a bunch of questions about challenge trials, but before we do that, because we are a bunch of lawyers here, Jen has a question about possible legal claims.
UNKNOWN:Okay.
SPEAKER_03:Yeah. So I was wondering whether participants have any legal claims based on any negative side effects that they might have experienced from participating in the trials or if their participation requires a future waiver of any claims that they could bring. And how does this, if at all, play into considerations of the ethics of paying volunteers for these trials and just like the legal risks of payment for the trials?
SPEAKER_05:Yeah. So there is, In the common rule that I mentioned, one of the requirements is that informed consent cannot include any exculpatory language. So you cannot be asked to waive any right that you would otherwise have. You cannot say in the consent form, by signing here, I agree that I'm not going to sue the investigator. I'm not going to sue Penn, blah, blah, blah. You cannot put that in your consent form. However, it is very... difficult for a research participant to successfully litigate if they are harmed from the research, so long as there's been adequate disclosure of the risks that could potentially befall that participant. So what the legal claim would be something like, you know, breach of breach of contract, breach of informed consent would be like a put the contract bit of an aside, it'd be a medical malpractice case, right? And so the researchers might have a duty to minimize the risks, right? Maybe they've breached that duty and maybe that caused some harm. But if the participant knew what the risk was and agreed to participate Anyway, they would have a lot of difficulty. They would have a lot of difficulty winning their claim. The other thing that makes it quite difficult is that you have the IRB signing off and saying this was a reasonable thing to do. Right. The investigators checked all their boxes and they did all the right things. They had the right precautions in place. And so research is uncertain. Sometimes people get hurt. So maybe there was no breach of duty at all. So research litigation is actually... very unusual, meaning the research participants suing the investigators. There, you know, there have been instances where research participants claimed that they were promised something. This is why I mentioned the breach of contract. You know, I was promised that I would be allowed to continue receiving this investigational agent, even if the study was closed early. For example, there was an example of litigation where participants claimed that researchers had promised them something that eventually was not provided, but kind of the run-of-the-mill research-related injury that's not being litigated.
SPEAKER_08:A number of questions about challenge trials. I'm going to let Mary start us off.
SPEAKER_04:Hi, yes. I was just hoping you could give us an overview of why challenge studies are particularly useful and can be necessary as opposed to other types of studies, and also why they would be useful for studying COVID in particular. I think it's a It would be helpful for a lot of our listeners and myself as well, just to understand. Yeah, it's like, so we're infecting people with viruses. We're infecting people with COVID. There's a lot of risk here. Why would we do
SPEAKER_06:that
SPEAKER_04:to people?
SPEAKER_05:So let me go way back, right? So some of the earliest challenge studies weren't called that, but it would give you a Allow mosquitoes to bite somebody with yellow fever and then allow those same mosquitoes to bite a healthy person to see what happens. Right. And that is, you know, a study that that was done by Walter Reed, the yellow fever experiments more than 100 years ago. And actually, yeah. He paid. He paid people to participate in those studies. Another historical example of a challenge study. And so, I mean, why would you do that in the yellow fever instance? Because you weren't sure how the disease was being transmitted. And so it would help you learn something about viral transmission. Another challenge study. happened in Guatemala after World War II. So the researchers who were involved in the study of syphilis in rural Alabama, well-known as the Tuskegee syphilis study, also were doing research in Guatemala. Maybe you've heard of this. It did not become known to the public until the early days of the Obama administration, but they went to Guatemala and with the intention of studying prophylaxis against various STDs. And they went to Guatemala because at the time, people who were in prison were allowed to have visits with sex workers, and those sex workers were licensed and regulated by the government. And so they could control the sexual relations that were happening, and they could see who was being exposed to these different diseases. Why would you need to do that if you were studying prophylaxis, right? Well, If you want to know whether your prophylaxis is actually effective, you have to know that people are being exposed to the pathogen of interest, right? Because if you give them the prophylaxis and they stay healthy, is it because they weren't exposed or is it because your prophylaxis works? So they thought, well, isn't this convenient, right? We can control who's having sex with whom and we'll know who's infected. But it turns out that it is Hard to get prisoners to cooperate, and it is harder to transmit these STIs than one would have thought. So they got rid of that approach. They ended up manually inoculating prisoners and other vulnerable populations with these pathogens so that they could eventually move into studying prophylaxis. extraordinarily shoddy science. It was kept secret for decades. It was uncovered by a historian of the Tuskegee syphilis study who was going through one of the researcher's files and said, oh my God, in the Tuskegee syphilis study, Are you saying
SPEAKER_08:there was a common researcher across Tuskegee and the Guatemala? Yes. Okay. Oh my gosh. Yes. Okay.
SPEAKER_05:Yes. So in Tuskegee, nobody was intentionally infected with syphilis. These were people who had syphilis and were allowed to go untreated without their knowledge and pass it on to others. But in Guatemala- they were actually intentionally and without consent infecting or exposing people to these pathogens, okay? But the reason that they were doing it was a... They did terrible science. Again, can't be clearer about that, but they have a scientific reason to do it. Wildly unethical. But there are lots of good reasons today why you might do challenge studies. And I think at least one of you mentioned that you knew somebody who had been in challenge studies. So these are fairly common for diseases that are mild, self-limiting, or we know how to treat. Common cold, influenza, malaria, typhus, I'm pretty sure. And They are ways of learning about pathogenesis, right? How does the pathogen interact with its human host? And they are ways of rapidly testing different potential prophylaxis or other types of interventions. And they can be extremely helpful when you are unable to do what's called a field trial. So in the context of Zika, we had a flare-up. But this is something that comes and goes seasonally. It's not something that is always affecting a large portion of the population. So if you wanted to study a vaccine for Zika, you might not have anybody getting exposed to Zika, right? You might need huge amounts of people to be enrolled in your study in hopes. I mean, in hopes. I don't mean that literally, but scientifically, you need some of them to be exposed to Zika in order to... see whether the vaccine works. But if there's not a lot of Zika virus floating around, then how are you going to study that vaccine so it will be ready for the next flare, right? So that was the part of the idea during COVID. Not that we couldn't do a field study, right? There were plenty of people and we did obviously, in fact, do field studies of the vaccine. But the idea of why people were, some people were excited about SARS-CoV-2 challenge studies were several. We didn't know how much viral exposure did somebody need to become infected. We didn't know what was the actual incubation period from exposure to showing symptoms and being infectious. We, at the beginning of the pandemic, had literally hundreds of vaccine candidates that were under consideration. If you could, instead of doing an a clinical trial with lots of different patients, giving them these investigational vaccines, letting them go out in the world and get exposed to COVID if they were going to get exposed to COVID. Do you know how many people that would take for the number of vaccines that were being considered? So the idea was, well, we would need far fewer people if we knew that they were being exposed to COVID. And that's what you do in a challenge trial. You knowingly expose somebody to the pathogen of interest. So the idea was rather than doing these larger studies with hundreds and hundreds of vaccine candidates, we could use challenge studies to what's called down select the vaccine candidates to then say, okay, these whatever number are reasonable to move on into larger studies rather than wasting our resources across lots and lots of them. Now, that was the, theory, okay? If we got COVID challenge trials off the ground in May of 2020, maybe they really could have sped up vaccine development. But you don't just go and expose people to COVID, to do it scientifically, you need to develop your challenge model, meaning you have to figure out exactly what strain of the virus you're going to use, how much viral exposure you're going to have, because you need to do that consistently, right, for the people that are actually participating in your challenge trial. That's why in the paper, we talk about human infection challenge studies. They're not always like a trial of some intervention, right? It could just be, The one that actually got done in the UK was a very small challenge study of 30 something healthy participants from the age of 18 to 30. And it was really just to help build the model. They exposed people to a very small dose of the virus. They watched them and saw how long did it take for them to develop symptoms. Half of them, I think, didn't get any symptoms at all. Those who did get symptoms had mild symptoms. They developed symptoms within an average of about two days, rather than like the four to five day incubation period that many of us have been thinking about when it comes to COVID. but they weren't even studying vaccines yet. They may go on to do additional challenge studies. The reason I'm mentioning this is that it takes a long time, right? So it took a long time to convince regulators, funders, ethicists that a COVID challenge trial would be appropriate. Then you have to develop the model. Then you would eventually get to studying vaccines. So if the idea is to speed up vaccine development, that social value drops off really quickly unless you have the model ready to go. And so now the argument is, well, maybe we need to do these challenge trials before we feel like they're necessary. That's when they're going to have their most social value because then we'll be primed to down select vaccine candidates for the next pandemic. So does that make sense? It's... It's a hotly contested issue whether it is reasonable to do challenge studies of emerging infectious pathogens. It is far less controversial to say, you know, we're going to do a common cold challenge study. We're going to do even, you know, malaria challenge study because you can rescue people really quickly if you know when they were exposed to malaria and they start to, you know, exhibit symptoms. exhibit adverse reactions. I will also say, there's not been any instances of death in a challenge study. They are fairly common for the more familiar diseases. And I could talk for a long time about whether there should be upper bounds of risk in research. We're asking competent adults to take a risk for the benefit of society. Just something that we ask people to do in a variety of ways, right? People serve in the military, people are firefighters. And so the real question in my mind about challenge studies is whether they in fact have enough social value to counteract the risks that might be associated with them.
SPEAKER_08:So Holly, that is, first of all, the most helpful and clearest explanation of the usefulness of challenge trials that I think are challenge studies. I'll start calling them that now that I've ever heard. So thank you for that. Given what you just told us about the UK study, and Ryan is going to have some follow-up questions, I think, about some of the specifics of that. I continue to hear ethicists or infectious disease experts complain about the UK study being unethical. And Let's leave aside whether the social benefit is sufficient, unless you want to address it. I don't know the answer to that. But I am always a little bit puzzled at the reaction given... Now, the fact that nothing bad happened doesn't justify taking too much risk. But nonetheless, it does... I mean, it's as if that part isn't discussed. I don't know. I just, I'm a little, I am sometimes puzzled by the way in which it is discussed among some members of the, say, infectious disease community or some bioethicists.
SPEAKER_05:Yeah. So I can kind of argue both sides of this. So I was not somebody who was categorically opposed to doing a SARS-CoV-2 challenge study. My Primary concern was how could we minimize the risks? Right. You know, what could we do to know as much as we could about the virus so that we could say we've got to exclude X, Y and Z demographic groups? And then the other thing I was really concerned about is, is it worth it? when we don't have a cure, when there could be unknown long-term consequences, somebody could have died. These were very real questions about whether you could ethically justify a SARS-CoV-2 challenge study. There were others who were strong proponents of it saying, so for example, some of you may have heard of this entity called One Day Sooner. One Day Sooner is an organization that was founded in the early days of COVID as proponents of doing SARS-CoV-2 challenge studies. And they've now moved on. I mean, they're still talking about SARS-CoV-2, but they've now added other types of infectious diseases that may be helpful to do challenge trials around, like tuberculosis, for example. And their argument was one day sooner, if we could get a vaccine even one day sooner for COVID, several thousands of lives could have been saved in the early days of the pandemic, right? And so it was frankly like a very, utilitarian argument. They weren't saying to hell with the risks. If we kill 30 people, that will be worth it for vaccine development. They weren't saying that. They were saying the risks could actually be minimized to the point of reasonableness. We could ask competent adults to take on that risk and that sacrifice, and we could save so many thousands of lives if we move this along fast. And their major frustration was people like me saying it's all about social value. It's all about social value, but they face this delay in getting those challenge studies up and running. And that really inhibited its social value. So they did the, they launched the UK study, I think in January of 2021 and results were reported at the beginning of 2022. Right. So we were already deep into the pandemic. People had, you know, been vaccinated, who are going to be vaccinated. We had kind of like moved on at that time. So they were frustrated by the fact that it could have had great social value if we did it earlier. The social value was reduced because of all of the consternation about the ethics of it delaying.
SPEAKER_08:So both of the things you said, let's focus on minimizing risk and let's seriously ask the question of, is it worth it? Make perfect sense to me. This is why I wanted you on here is because you make sense to me. What didn't make sense to me was, I mean, we asked people to take all sorts of risk during COVID and they did. right? Healthcare professionals, obviously, but everybody from food service workers to, I mean, it's like sort of all sorts of people continued to take risks during COVID. And I'm not sure, and probably we should have been asking more careful questions about whether all of that was worth it. I don't mean for healthcare workers, but in some other industries, perhaps we should have been asking. The fact that infection is intentional rather than probabilistic just doesn't strike me as changing the ethical question in as significant a way as many people seem to believe. Although I completely agree with your two questions about like, let's make sure we minimize the risk and let's make sure it's worth it. That makes sense to me. My puzzlement at some these conversations.
SPEAKER_05:They, this one day sooner organization, they had a signup page where people could say, and they got tens of thousands, tens of thousands,
SPEAKER_06:so
SPEAKER_05:many people. And one of the really interesting things that people said was, I feel so helpless if the, you know, in the early days of COVID, well, lots of people still feel helpless just kind of watching how things have played out. But, you know, in the early days of COVID, especially people saying, well, I feel so helpless. I'm not a doctor. I'm not on the front lines. I can't really help. This is a way that I could help.
SPEAKER_08:Right. Especially for young, healthy people where the, you know, the risk's not zero, of course, but it's the risk of a severe adverse outcome for them was lower.
SPEAKER_05:And there were other people who say, you know, look, you'd let me go like skydiving, bungee jumping, riding a motorcycle without a helmet. You know, I'm allowed to do all of those things. Why couldn't I do this? less risky thing that has the possibility of helping someone, right? So there was also an argument behind it.
SPEAKER_08:Right. Tune in for part two of our interview with Holly Fernandez-Lynch in the next episode, where we continue our discussion of challenge studies and also explore issues of coercion, inducement, and exploitation in clinical research.
