IBD Drive Time: Ethical Issues in Clinical Trials

In this episode of IBD Drive Time, guest host David Rubin, MD, calls on Drs Severine Vermeire of KU Leuven University in Belgium and Dan Tucker of Hebrew University of Jerusalem to talk about the challenges of recruiting patients for clinical trials in inflammatory bowel disease and the ethical issues involved.

David T. Rubin, MD, is the Joseph B Kirsner Professor In Medicine, chief of Gastroenterology, Hepatology and Nutrition, and director of the Digestive Diseases Center at the University of Chicago School of Medicine. Severine Vermeire, MD, is a professor of medicine and head of the Department of Chronic Diseases & Metabolism (CHROMETA) at Catholic University of Leuven in Leuven, Belgium. Dan Tucker, MD, PhD, is professor of pediatrics at the Hebrew University of Jerusalem, and director of the Pediatric IBD Center and research unit at the Chariot Zedek Medical Center in Jerusalem, Israel.

Any views and opinions expressed are those of the authors and/or participants, and do not necessarily reflect the views policy or position of the Gastroenterology Learning Network, or HMP Global, its employees, and affiliates.

David Rubin:

Welcome to IBD Drive Time. My name is David Rubin. I'm a professor of medicine at the University of Chicago, and I have a secondary appointment in the MacLean Center for Clinical Medical Ethics, which is of particular relevance to the topic we'll be covering today. Today I'm joined by two world renowned experts in IBD, and we're going to be discussing the ethics of clinical trials in IBD.

I'm really excited that joining me are both Professor Séverine Vermeire and Professor Dan Turner. Séverine Vermeire obtained her MD degree at the Catholic University at Leuven, Belgium in 1995, and then her PhD, subsequently, and she's currently a full professor there. She's known throughout the world for her research and leading efforts in clinical trials and bringing new therapies to the field of inflammatory bowel disease, but also in studies that have led to better understanding of the mechanisms of inflammatory bowel disease. And I'm really delighted that she's here today for this topic with us. Hi, Séverine. How are you?

Séverine Vermeire:

Hello, David. I'm fine, thank you. And thank you for having me for this interesting podcast.

David Rubin:

You bet. My second guest is Professor Dan Turner. Dan is a professor of pediatrics at the Hebrew University of Jerusalem, and holds a PhD in clinical epidemiology from the University of Toronto. He's been the head of the Pediatric Gastroenterology and Nutrition Unit at the Shaare Zedek Medical Center in Jerusalem since 2008, and he is the director of the Paediatric IBD Center and Research Unit there. He's also co-chaired the European Crohn's and Colitis Organisation and European Society for Paediatric Gastroenterology Hepatology and Nutrition guidelines for the treatment of children with IBD. So you can see that Dan is a perfect guest to be joining Séverine and me to talk about this topic. Hi Dan. How are you?

Dan Turner:

Hi. Good evening. Good afternoon.

David Rubin:

Well, I'm delighted that both of you are here and we have had our group and individual conversations about clinical trials in IBD, and how we can get new therapies to the patients who need them. I thought I would start with just a general question so we get everyone on the same page. What are the current challenges to recruiting patients into the clinical trials of IBD? And maybe, Séverine, you can start us off there.

Séverine Vermeire:

I see a few challenges, David, certainly in our center, which is a referral center. It becomes increasingly difficult to find or identify patients that have not been exposed to too many treatment options, or in other words, that have not become too refractory. That's certainly one challenge. And then, of course, the challenge that always remains with trials and randomizing patients is the fact that there is placebo as part of the trial, at least in the beginning.

David Rubin:

And we've had some problems. The numbers quoted have been as low as 0.1 adult patient per site per month getting enrolled into some of these pivotal trials. So you can do the math—in a study of 700 or 800 patients, how many sites you might need and how long it can take to actually enroll successfully. Dan, what are the other challenges that you might add to the list?

Dan Turner:

Placebo for sure, but I think the harsh eligibility criteria in general is a big problem, especially in children. But generally—and I would name 2 in particular—one is a long washout period from previous biologics. So if you need to have 8 weeks since the previous biologic and the patient needs to stay in a moderate to severe status, otherwise is not eligible for screening, then if you have valid alternatives outside the trial, so very few patients will choose this path. And the other criteria which is problematic on the same page is the long screening period. So once they finish their washout period and you start screening and you wait another 3 weeks or 4 weeks until everything comes back from the central lab and the cell to reading and until this happens, many patients just drop out and they just require treatments outside the trial.

David Rubin:

So on the one hand, it's nice that we have some newer options and many options for some of our patients to consider treatment for their Crohn's disease and ulcerative colitis. On the other hand, we recognize that those options are often being preferred over exploring new treatments and especially when patients have to be screened so rigorously or when inclusion criteria are too strict.

So what's the whole purpose of placebo? Séverine, what are the benefits of having placebo arms in clinical trials, maybe more historically than currently, but can you just briefly mention why the FDA or the EMA have favored placebo?

Séverine Vermeire:

Yes, sure. Of course, we know that placebo provides a greater scientific reliability of the results of your trial. So from a methodological point of view, there certainly is an advantage of having a placebo in the trial. The potential efficacy, I think, of a drug can really be observed without exposing too many patients to a potentially new treatment. And this is the big advantage, I think, over noninferiority trials, the need for a lower sample size to really show or demonstrate an effect.

David Rubin:

So I think that's an important point. The concept of noninferiority is something we don't talk a lot about. But in general, you need a much larger sample size to show that 2 treatments are not inferior to one another. Or another way to say that is that neither is superior to the other than when you have a placebo arm. On the other hand, it raises the question of clinical equipoise, or whether there's an equal likelihood in the investigator's mind that the patient may or may not respond to either arm of the trial. So Dan, how do you approach the question of clinical equipoise when there's placebo or maybe you don't think there is any longer?

Dan Turner:

Personally, I don't think there is anymore. We managed to ditch placebo in pediatric trials a few years before when we united all pediatric organizations and members in a global campaign. We discussed this with the EMA and the FDA, we wrote position papers. We voted more than 100 voting members of 5 organizations globally with a consensus of 93% that placebo should not be used in pediatric trials. There was one trial from adalimumab in ulcerative colitis that was the first one with placebo, and none of us enrolled patients to it. And after 2 or 3 years, they had 17 patients in that trial. And I think that's when the FDA understood that there is a problem. And since then placebo is not part of any pediatric IBD trials.

If you ask me, I don't think this should be part of adult trials as well. I'm saying this with all the modesty needed because I'm a pediatrician. And some cynical adult IBD tell me, "It's nice for you because you rely on historical or external placebo rates from adult trials. And if you ban that from adult trial, also the pediatric population will be hurt by this decision." I have something to respond to that, but maybe Séverine will be more adequate to address that.

David Rubin:

Well, of course, I know you're not referring to Séverine or me as the cynical adult investigators. But Séverine, will you think about this in adults? What's the potential harm of placebo in the modern world of enrolling patients in our trials with IBD?

Séverine Vermeire:

I do believe that there is potential harm of still having placebo because what happens in my opinion is that we are really driving the steroids up and a longer use of steroids because patients know that they have a chance of ending up receiving no drug, the placebo, and they really know that they need to reach that primary endpoint, which is often placed at something like week 10, week 12, or sometimes even later. So patients really want to make sure that they reach that endpoint, and so they will take steroids or ask for steroids. And so most of the trials also demand that then the steroids are being continued or kept stable during the entire induction period.

So I really think it is dangerous to keep patients on nonactive drugs or placebo. It drives steroid use; that will also increase safety events as well. And we have seen in some trials in Crohn's disease for instance, some perforations that were not linked to the drug but were linked to ongoing active inflammation. So I really believe whereas the declaration of Helsinki allows the use of placebo when there is no alternative, I think, nowadays, as also Dan said, we have multiple other options available that the use of placebo in, my opinion, is no longer justified. So I really hope that also the adult IBD field will follow the pediatric fields.

David Rubin:

As you see, the pediatric folks got organized, and they voted with their feet. And I do agree with you. I think when you consider not just the harm of being on placebo and progression of an active moderate to severe disease, but also what you just mentioned, which is concomitant steroid use and the adverse events that go along with that. The other point of it is it defeats the whole point of what the regulatory agencies and pharmaceutical companies have tried to say, which is, "If we use placebo, we can study fewer patients and get the drug through the process faster." In fact, as you know, Séverine, you and I together are part of a steering committee that just analyzed a phase 3 trial that didn't meet its statistical primary endpoint because the placebo rate was too high, and maybe it was because those patients needed more steroids. So it's a big deal.

IBD Drive Time is sponsored by the Gastroenterology Learning Network and Advances in IBD. Don't forget that the Advances in IBD meeting is coming up this December 2023 in Orlando, Florida. You can find the podcasts of the IBD Drive Time on Apple and Spotify. Just search for the Gastroenterology Learning Network to find us.

I'm back now with Professor Séverine Vermeire and Professor Dan Turner, and we're talking about some of the ethical challenges of clinical trials in IBD. So Dan, you taught us that the pediatric community got organized to argue the case against placebo arms in trials for children with inflammatory bowel disease. What were the potential solutions that were proposed and how are you doing trials now?

Dan Turner:

The first intuitive solution was to use external placebo rates. And that has been used from adult trials because there are not enough placebo trials in children to use historical placebo rates. But now with dozens of RCTs in adults using placebo, and placebo didn't change with time more or less, you can have a meta-analysis of placebo rates in the various RCT and adjusting for the baseline characteristic of the enrolled patients, and then you can have a more or less fixed rate of that specific population you have with disease duration and the mixture of severity of the patient. That was the first solution.

The second solution, which is now materializing, is platform designs. And platform designs needs to be adopted from cancer management. My response to people say, "You have to have placebo, otherwise you don't have a very solid benchmark," I said, "Well, we're introducing all the time new chemotherapy and biologics to cancer and there is no placebo in cancer management." There is something to learn from this field. And there is the first trial in pediatrics with the platform design with IL-23 blockers is about to be launched these weeks. And the platform design says that you use Bayesian statistics and one patient comes in and you assess the likelihood of this patient to respond comparing to the different medication there is in the platform. So you have the same protocol, the same centers, just different medications. So that also shortens the time to engage centers into the trial, and you learn the rate of the new patient compared to all other treatments to that platform.

And in cancer, and it could be the same in IBD as well, you enter the biomarker of your cancer, and then the platform will select the right intervention for your biomarker. And we are starting to enter that phase as well for IBD. And then once the Bayesian statistics identify that the new intervention is futile, it will say, "We have to stop." It could be after 20 patient, 30 patient, 40 patient, no placebo, or when it is convinced that this is actually not futile, it will exit the platform and then you can continue with the phase 3 confirmatory trial. And this is already materializing in pediatrics because of our rebellion campaign and the first trial is going to start soon.

David Rubin:

That's great, Dan. Thank you for explaining that so well. And obviously, we would love to have more validated, or at least possible therapeutic biomarkers to guide inclusion. We've seen a little bit of that in the phase two trials with TL-1A inhibitors, and perhaps we're going to see more of those coming, which would obviously help us understand who might be the better candidates for certain mechanisms. Séverine, can you add? What do you think are some of the creative solutions we can have to limiting placebo exposure in trials?

Séverine Vermeire:

I think we simply also need to think more of having active comparator trials before really approval. Now we're having those after the drug is approved, but we don't need any me-too drugs, right? We need drugs that are significantly better and having a better efficacy and safety to the options that we use daily. And now with having at least 5 different MOAs that we have really been familiar with, I think new drugs should just explore their efficacy and their safety against some of these 5 MOAs that have become our standards now. So I see well that anti-TNFs, or vedolizumab, or perhaps ustekinumab and IL-23 may become the standards, and we are comparing against these standards. And new drugs need to show that they are, at least I would say, and then it comes to what is at least, is it 10, 15%, 20% better and as safe or safer? So they need to show an added value. We really need to step away from having a sixth MOA with a similar efficacy and a similar safety.

David Rubin:

I do agree with you. And there's a lot we can learn from the cancer experience. One is, of course, that they protocolize most patients, and they're organized in that regard. And some say, "Well, that's because they can do molecular tumor and tissue typing." But honestly, they started doing that way before they had those markers, and those came because they were organized and protocolized. And I think it would be a big lift, but it's certainly something in IBD we should be exploring more actively.

The other, of course, when you talk to patients is both a therapeutic misconception of what we're trying to do in trials as well as the aversion to having too many interventional procedures like colonoscopies, and the advent of things like intestinal ultrasound as endpoints or other surrogate and appropriate markers, I think, can make trials more acceptable to patients and successful for all of us.

So that gets me to my last point for today, which is to ask both of you, how do you talk to patients about participation in a clinical trial? What do you tell them? Perhaps, Séverine, you can start. And then, Dan, you can tell us how you do it, talking to parents and patients.

Séverine Vermeire:

It's a very difficult one, really, and certainly the placebo aspect is difficult to explain to patients. We try to engage patients early on in participating into trials and not wait until they have really exhausted all of the therapeutic options because then, of course, when nothing else is available, it's easier to perhaps accept a trial with a new drug including placebo. But it's not very easy and it requires a kind of altruism, I would say. And I also tell patients that the drugs that perhaps they are receiving now were approved on the market, thanks to other patients that were in a similar scenario and have really accepted to take part of the trials. And because we had those pioneer patients and the drug is now on the market and has benefit perhaps the patient who's sitting in front of you. So if each patient can perhaps be a little ambassador for a next patient, and if we can create that kind of altruism for the community of patients, this helps.

So this is what we are trying to do. Get them really involved in the bigger research we are doing, and that includes, of course, basic and translational research, but also the clinical research. And then you are sometimes surprised about the generosity and the willingness of patients to really contribute to science and making the scientific field progress.

David Rubin:

I agree completely. In general, in my clinic and over my career, I've found that patients want to participate or want to help. It's the challenge of participating in interventional therapeutic trial, certainly in the U.S. and in a tertiary center as we've discussed, that brings us new problems to address. And I do discuss with patients the option to pull out of the trial at any time, that they can get open-label drug, that maybe there's a 4 to 1 randomization scheme where they're less likely to get placebo, but it keeps coming up as a challenge for us and we're now looking at what those harms are across all our trials so we can quantify this. Dan, do you have any tips and pointers about how you do this? Now you don't have to talk so much about placebo, but how do you get parents and children on board for clinical trials?

Dan Turner:

So with parents, it's more difficult because the altruism that, Séverine, you talked about is the basis for any enrollment in clinical trials. But by law and by ethical rules, parents cannot be altruistic on behalf of their children. They have to make decision for the benefit of that specific child. And this is a controversy. After the age of 18, you can decide to compromise with your help to help other people. A parent cannot do that for their children, otherwise is violating the basic rules of being a parent.

So every trial that is being initiated in pediatrics needs to have an added benefit for the patient and for the child. And often it's easy to achieve that if we think that the trial needs to mimic the way the patient's actually being managed in clinical practice. Sometimes they have an early escape to combining biologics, maybe think that they cannot have access as part of clinical practice, no placebo, short screening period, easier access to drug levels or other things that may be more difficult to achieve. And if we think about it like that and you say, "This is a trial that I would be happy to or I will be favorably considering to enroll my child into that trial," and then it's easier to reflect that to the parents themselves.

David Rubin:

This has been such a good conversation, and I knew I had the right guests when I invited both of you to talk about it. Obviously, there's still a lot of unmet needs in IBD, and so we need to move forward in a thoughtful way to engage our patients and enroll folks in clinical trials so that we can do better for our patients and do better for the field. And so I think that this conversation and others that we're having now should move the field forward, and I look forward to working with both of you to advocate for improvements in the way we do these things.

I want to specifically thank my guests, Professor Séverine Vermeire, who's with us from the Catholic University in Leuven, Belgium, and a world expert in the clinical trial space, and Professor Dan Turner who's at the Hebrew University of Jerusalem and equally expert specifically in the pediatric IBD space, but has influenced our field on the adult side very much as you've heard today. Thank you both for being here with me and for all you do for our patients.

Dan Turner:

Thank you, David.

Séverine Vermeire:

Thank you, David.

David Rubin:

This has been IBD Drive Time. I really enjoyed it, and I hope that you'll join us for the next episode. Take care.