Navigating the Tensions: Maintaining Pragmatism and Ethical Principles in Research and Development

Ayden Eilmus

All right so I think in the interest of time I'm going to get started and then we'll let people join as introductions are kind of taking place. So hello everybody and welcome to PGTME's sixth annual lunchtime lecture series. My name is Aidan Eilmes and I'm the program coordinator for the working group on pediatric gene therapy and medical ethics or PGTME as we like to call it. PGTME is a project of the Division of Medical Ethics housed in NYU Grossman School of Medicine's Department of Population Health, and is funded in part by a gift from Parent Project Muscular Dystrophy. You can learn more about PGTME at the link to our web page, which will be put in the chat. The Lunchtime Lecture Series, or LLS, is our hallmark educational event. It's been happening throughout the entirety of this week. Please join us tomorrow for the last day of the series from 12 to 1.15. for a session called Improving Patient Access for Gene and Cell Therapies, a Financial Engineering Perspective, which will be presented by Andrew Lo. And a registration link for that will also be put in the chat. Thank you so much for being here today for our panel, Navigating the Tensions, Maintaining Pragmatism and Ethical Principles in Research and Development of Genomic Medicines. Please note that this session is being recorded and it will be posted on PGTME's YouTube page next week, along with recordings from the rest of this year's lunchtime lecture series in case you weren't able to attend all of them. So today's event will feature some introductions of our speakers, followed by a moderated discussion. We've allowed for at least 15 minutes of Q&A and encourage you to put audience questions using the Q&A feature at the bottom of your screen throughout the duration of the session today. And so without further ado, I'm going to introduce our moderator and then hand the mic over to him. Dr. Rafael Escandon is the principal and founder of DGBI Clinical Research and Ethics Consulting on Bainbridge Island, Washington. He's worked in global clinical research and development and patient advocacy in the biotechnology industry for nearly 30 years. His approach is to be highly considerate of the ethical implications of conducting and participating in clinical research, especially in rare diseases and in vulnerable and developing world populations. And of course, he's also a member of PGTME. So with that, I'm going to pass it over to Rafael to get us started. Thank you so much to all of our speakers for being here today.

Rafael Escandon

And thank you, Aidan, for that great introduction and for all the coordination that you've done all week and will do for the remainder of the week, too. And thanks as well to Lisa Kearns, who's behind the scenes, always a good force for us here. Good morning from the Pacific Northwest. Good afternoon and every time zone in between. As Aidan said, I'm Rafael Escandon. And you'll likely see me sipping my coffee periodically here as I try to moderate a discussion between two friends and colleagues from the PGTME.

Rafael Escandon

What I'll do is I'll introduce them first, and then I'll mention a few points about how we've attempted to structure today's session, including a brief slide presentation from me that really tries to, again, keep ourselves grounded, which I'll talk a little bit more about in a moment. But let me first introduce my friend and colleague, Dr. Emma James, who is on your screen there as well. Emma is vice president of clinical and medical affairs and head of the medical office at Encoded Therapeutics, which is a biotech company that's developing gene therapies for children with central nervous system disorders. Emma obtained her PhD from the University of Oxford after completing her research at its Nuffield Department of Medicine and Wellcome Center for Human Genetics. With the majority of her career spent at small and mid-sized biotech companies in the UK, Boston, and now in San Francisco, Emma has spent more than a decade specifically developing gene therapies for rare pediatric genetic disorders. In 2018, she was awarded honorary membership of the Faculty of Pharmaceutical Medicine in the UK and the Royal College of Physicians in recognition of her many contributions to pharmaceutical and biotech medicine. So thank you for joining us and for being on the PGTME, Emma.

Dr. Emma James

Emma needs to write a shorter

Rafael Escandon

bio. That's OK. All warranted. It's important background. And so beside Emma on your screen, between Emma and me on this, at least on my screen, is Dr. John Lantos. John is a bioethicist and a primary care pediatrician in New York City. He was formerly professor of pediatrics at both the University of Chicago and the University of Missouri. His research focuses on innovative treatment for children, and he's written about ethical issues in neonatology, oncology, endocrinology, and genomics, to name just a few areas. John was a co-principal investigator of a National Institutes of Health-sponsored study of newborn sequencing in genomic medicine and public health, and a PCORI-sponsored study of community-driven participatory research in genomics and rare diseases. From 2013 to 2016, he served as co-chair of the PCORI Clinical Trials Advisory Panel and was an advisor to the American Academy of Pediatrics Primary Care Research Network. John was also past president of the American Society for Bioethics and Humanities and the American Society of Law, Medicine, and Ethics. John has the additional distinction of having served a few years ago now as one of my professors in pediatric bioethics. And then finally, John's most recent book, Kidney to Share, examines ethical issues in living kidney donation. So thanks to both John and Emma for agreeing to participate today.

Rafael Escandon

So at the core of today's session, when we were planning it, I took some inspiration from the spirit that's embedded in this quote, which actually the quote itself is interesting because there are numerous, if you ask the language learning models, AI, different AIs give you different answers as to who may have said this, but it's really a, I think it's an amalgam. So the quote is, in theory, there's no difference between theory and practice. But in practice, there is. So that's really been the sort of common thread in the spirit of what I think we're going to try and get to today. And we've got a lot of different touch points. So I'm really going to try to integrate those in our discussions.

Rafael Escandon

our approach, as I said, will really be to discuss the ethics and practicalities at several logical touch points along a continuum of how a genetic intervention is developed from choosing the Medellin disease target to getting into and through clinical trials. And then finally, into the long tail that stretches beyond the trials themselves to regulatory approvals and beyond. As I've mentioned, I think I'm going to Barry basically set the table by presenting a few slides as sort of a launching pad for the topic discussions. And in those discussions, I hope to serve myself really more as a facilitator between Emma and John.

Dr. John Lantos

Emma

Rafael Escandon

as a genetic medicine developer, and John as a pediatrician researcher in bioethics, while remembering that the three of us are all members of the PGTME. So as I said, our hope today is to try and maintain a bit more focus on the fundamental ethical principles and the realities and implications of their practical application in genetic medicine research and development. And we're going to try and apologies in advance for failing at this because I'm sure we will, but we're going to try to steer clear of discussing specific technical and specific regulatory strategies and try to keep each other in check if we start heading down any of the literally hundreds of rabbit holes that we could walk into. In addition to our selected topics, along the continuum I mentioned, we do very much want to hear your questions. So please fire away in the Q&A. I'll be monitoring that very carefully. And so all week, the questions that have come in have really enriched the discussion. So we want today to be no exception to that. And then finally, I think if we're really, really, really lucky, We hope to even add some color to the great discussions that have been had so far this week and Mondays through Wednesday's sessions. And if we can enrich those, I think we'll be really successful as well. So, you know, in theory, we'll be highly organized, you know, and have a rich and meaningful discussion on every topic that comes in that we have planned and that will come in on the Q&A.

Rafael Escandon

But let's see what happens in practice. So now I'm going to present a few slides just to, as I said, get the ball rolling here. Get

Rafael Escandon

this into presentation mode. Just give me a thumbs up if you can see the slides. Okay, great. Get it into presentation mode again. Whoops, let's go here. Okay, so... This is a slide that I really try to illustrate one main point, which is on the right-hand side, gene therapies or genetic interventions, even though the research and development rubric is built upon one that started with small molecule drugs and then was adopted by biologics, these interventions are really, really, really different from each other. And whether you're talking about what they are themselves, simple things like their mass, how they're made, their routes of administration, how they actually work, their costs, their storage requirements. I mean, these interventions are very, very, very different from each other. And so we're really going to focus on the right-hand column here, genetic interventions, and really think about the implications that every one of these small differences has in how these interventions are studied, developed, and then ultimately used in medicine if they are approved and adopted into a treatment paradigm.

Rafael Escandon

Just to hit a few of the big differences from an ethical perspective, this sort of ethically distinguishing features of gene therapies and gene edits, just remember, of course, that they are highly targeted to a specific gene or a specific mutation. Many of the discussions and most of the discussions that we have at PGTME have traditionally been related to viral vector-based gene therapies. There are some emerging technologies, which we'll talk a little bit about, I think. But the bottom line is that these vectors are used to deliver the genetic cargo to the target cells, depending on where those are in the body. So because you're giving trillions of viral particles, typically, previous exposure to that vector would be disqualifying because the immune system would, of course, destroy the vector the second and any subsequent times you see that. So that doesn't allow redosing to be part of sort of the current continuum of feasibility, which is really...

Rafael Escandon

one of the biggest unique characteristics here is that you get one shot with these interventions and so that's really really important and as part of our discussion similarly once these are administered you can't modify them or at least currently can't really you don't really have modalities to modify them you can't turn them up you can't turn them down you can't turn them off you can't you can't take them away so these are um these are really These have implications not just for modifying the efficacy potentially or the toxicity, but a patient that has participated in a clinical trial really can't discontinue or the definition of discontinuation is very different than it would be if you turned off a drug. Similarly, the next two bullets, immunosuppression is generally required. You heard yesterday, and there was a really nice opinion piece that dropped in molecular therapy yesterday or the day before that talks about immunosuppression. It's very much sort of contiguous with the transplant populations where it's really a requirement. There isn't a lot of,

Rafael Escandon

let's say, alignment on immunosuppression. regimens depending on which disease or which vector is used. So there are big differences. So that sort of portends the possibility of off-target sequelae that may happen, not just because of the vector or the transgene itself, but also because of the immunosuppressive regimens and other elements that you need to ensure that the body doesn't attack the transgene or the vector itself. The durability of efficacy and long-term safety of these is still largely unknown, which requires a long follow-up of five to 15 years in the clinical trial setting. Also in the post-marketing setting, there is a greater requirement for long-term safety monitoring. And interestingly, and something we don't talk about too often or in great detail, but traditionally, receipt of a gene therapy in an investigational setting tends to exclude you from uh tends to make its way into exclusion criteria for other investigational interventions be they gene therapies or possibly other interventions like enzyme replacement therapies and others so these are just some of the main ethically distinguishing characteristics that make i think we want to talk about and and as parents as participants as advocates as investigators really distinguish these interventions from from one another so on the other hand these are these can be these interventions can be truly transformative and so bearing those potential considerations and liabilities in mind we should also

Rafael Escandon

remember the potential benefits of these and how different they can be in terms of what they can perform. This slide is really going to be our sort of home base for today. We're really gonna try to walk through left to right the entire process of discovery to approval and some of the main areas that require at least some ethical consideration. from the early days to dose selection to follow up. And this can take years and be very arduous or with rare diseases, it tends to be a little bit more truncated of a process. But for a lot of the reasons that I just mentioned, each of these steps is a bit more complicated with a genetic intervention than it would be for a drug. Just to ground everyone on what a typical phase one first in human gene therapy study design looks like or has looked like. There are some modifications to this a little bit, but in general, when you're giving the first dose in humans, you start with one patient at a dose that we'll talk, I think, with Emma about the painstaking work that goes into choosing that first dose for a genetic intervention for the first in humans. You dose one patient, you assess it, on a timeline, depends a lot on

Rafael Escandon

what your biomarkers are or how you measure efficacy and safety, but you try to make an assessment as quickly as you can because patients potentially are waiting to participate in these interventions. But the general scheme is you dose a patient, you determine very preliminary safety, maybe some very preliminary efficacy, and if it looks good, you might dose one or two more. to, again, make those assessments. And if you think, if you're not seeing efficacy and it seems safe, you'll do the same thing at dose level two. That increment, not a lot, that dose escalation increment, it just depends on a lot of different things. We can talk about that, but then you repeat the same thing. Dose a patient, see if something good happens. If it does, dose a few more. you can expand out that cohort. Maybe you've gotten lucky and you found your dose. If you haven't, you escalate again in a similar fashion. But anytime anybody gets a genetic intervention, they are enrolled into a long-term observational extension. So what does transformational look like in terms of a gene therapy? I love this slide. And it's not to plug a particular program, but I think it just illustrates that dose escalation first in human model. This is Zolgensma. This was their first in human study. On the vertical axis here is the efficacy endpoints, the CHOP and TEN score. It's a motor function assessment. And you can see that in their first, think of this as dose level one, they dosed three patients and made the CHOP and TEN score assessments all along the... This timeline here. And so what you can see is that there really is no efficacy effect here. So they escalated the dose to dosing cohort two. And wow, not subtle, right? Potentially transformative. Big, big, big. efficacy response by these patients in this trial. Also learned a little bit on the patient at the bottom right there, seems to have defined a window of opportunity in terms of age and months for these patients. So a lot learned with a small number of patients in a very severe condition, but you could argue that at least in the short term that this represents a transformative effect.

Dr. John Lantos

Okay, finally, my last slide.

Rafael Escandon

What I tried to do was to sort of categorize, and this is what you get when you ask ChatGPT to generate an illustration of different stakeholders that are in tension with each other. And so what we're going to try to do, this being a little bit of a of an interesting representation. We chose to think that these people are singing rather than yelling at each other. But the bottom line is that things can become tense throughout the process. And so what we're going to try to do is to think of things through every stakeholder's perspective and really unpack what the fundamental ethical principles are and how we can apply them insensitive ways to really understand what an ethics committee, what patient participants and advocates are looking for, what physician investigators are looking for, what sponsors are looking for, and what regulators are looking for, just to name a few. That is it for laying the groundwork on today. I'm going to stop sharing at this point. Let's start with the left-hand side of the diagram in terms of just choosing the

Rafael Escandon

intervention or the disease state itself and thinking about just are there basic moral principles that would or should maybe go into that decision to choose a condition in the first place? And I'll ask John that question if anything comes to mind, you can kick it off. And then I think Emma will probably have some pragmatic thoughts on. So John, that question of like choosing a condition in the first place and sort of, you know, are there some, fundamental moral principles in that that we ought to think about or that you think have been done well or maybe might be improved?

Dr. John Lantos

Yeah, I mean, I think the primary consideration in choosing a condition is whether it's either life-threatening or so physically debilitating that

Dr. John Lantos

the risks of a first in human and potentially lethal intervention are thought to be justifiable compared to the alternatives. So, for example, spinal muscular atrophy, severe infant onset spinal muscular atrophy seems like it meets those criteria. Many children who have it die. Those who don't are ventilator dependent forever. And there was no effective treatment. That seemed like a good place to start. By contrast, and this isn't really a gene therapy, but it's an innovation for a congenital anomaly that was ethically controversial, in utero fetal surgery for myelomeningocele was one where the condition was not life-threatening, but the intervention might have been, and the hope was it would improve physical functioning and cognitive capacity. rather than extend life. So that was a much more controversial one. The more you get to that improved quality of life end of the spectrum, the harder it is to justify a potentially risky intervention.

Rafael Escandon

Yeah, yeah, definitely. You know, I had in my notes here a quote from one of my favorite

Rafael Escandon

O.G.s in bioethics, who's, you know, an interesting and complex person was himself, Harry Beecher, who said in his maybe one of his second or third most famous papers that no experiment is ethical unless the gain anticipated from the experiment is commensurate with the risk involved. So that's obviously a very sort of a purist approach. Right. And I think we often sit on the margins, as you just point out, of that. And in particular here with gene therapies or these genetic interventions,

Ayden Eilmus

often

Rafael Escandon

there are significant risks to the intervention itself. But in the context of those severe consequences, it's... we can make justifications for that.

Dr. John Lantos

Go ahead, John. Just one more point on that. Assessing the severity of the condition is the sort of problem that leads to the kind of reaction your last chat GPT generated slide suggests. Before gene therapy, when people were talking about bone marrow transplants for hemoglobinopathies, The question was, how severe is the disease and how much does it justify a potentially lethal intervention of stem cell transplant? And we did a study and found that both the doctors, the IRB, and the parents had wildly different opinions about how severe the illness was and how much of a burden it was to live with, and therefore, whether it met Beecher's criteria for the risk being worth the benefit.

Rafael Escandon

right right exactly so emma tell me about from a from a you know biotech development perspective the kind of conversations that you might have within a company or even within investigators um what uh about the the practicalities of say designing a trial in that in a disorder like that and what some of the uh the trade-offs or what some of the elements that the folks at the company might need to be prepared to think about and address?

Dr. Emma James

Sure, sure. So I guess, you know, when we're starting to look at new indications, I mean, firstly, we need indications that have a well understood biology so that we can actually design targeted therapeutics to address that underlying biology. And then we'll be looking at things like, you know, are there robust animal models to enable us to test potential efficacy within the animal models first? I don't know whether to go into that now, Rafa, or maybe that's a conversation for later.

Dr. Emma James

And then, you know, we're certainly looking at the risk benefits. Again, you know, when you're talking about these kinds of... interventions that you can't take away. You really want to be making sure that there is a sufficient severity, there is a sufficient unmet medical need that isn't treatable by other therapeutics to warrant the risk that people are going to be taking.

Dr. Emma James

And then as we talk about or think about moving that into the clinic, we want to understand the severity of the disease. Or what point is that optimal therapeutic window? You know, what would the endpoints be? And do we expect to be able to make a change in the specific endpoints over the time course of a clinical trial? Often clinical trials for gene therapies are much longer than for other disorders. And especially, you know, Firstly, we'll be looking at durability, but even just more pragmatically, if you're looking at things like, for example, cognition, we don't really know, firstly, what age do you need to treat that to be able to have that benefit? But secondly, how long is that benefit going to take to be seen? So we'll be looking at what could the endpoints be that can show regulators that the treatment is having the intended desire. A presence of biomarkers is also really, really important and really helpful with that kind of thing. And then the thing that, you know, nobody ever wants to talk about because it's

Rafael Escandon

you know,

Dr. Emma James

it it feels a little distasteful when you're thinking about ethics, but it really is kind of like how many patients are there. So firstly, you have the pragmatic the pragmatic question of can you actually run a clinical trial? I have been at a previous company where we we've started working on a disorder. And then it actually turned out that all of the patients were in a population that wasn't comfortable with these kinds of genetic interventions. And so we couldn't even run a clinical trial. But beyond that,

Dr. Emma James

pharmaceutical companies have to get funding from investors and if investors can't make money, Ultimately, we won't get investment, which means we can't we can't invest in these programmes and these programmes are very, very, very, very costly. And so there is that that that trade off of, you know, do we think that pragmatically we have a target? Can we design a clinical trial and run it and show results that are acceptable to regulatory authorities, acceptable to patients, clinicians and also payers to be able to. make some return on that investment and then turn that back into research and development for other disorders too. But it is a complex conversation that we have when we're trying to determine where do you start. I think larger companies often will try and have the small populations alongside bigger populations, which is perhaps a little more quote unquote altruistic. But for smaller companies, that can be harder to do. So there is, again, a balance between the commercial aspect and pragmatism and ultimately wanting to do the best thing for the patient community, which we do all want to do.

Rafael Escandon

Right, right. And so in terms of one just question to drill down a little bit on that is, what do you think, there's not a best way, but what are some of the best ways for you in medical affairs and in program development to ensure that the patient voice is heard within your company? And then how, what are the best ways to ensure that in all corners, in terms of company stakeholders understand reasonably what the lived experience is like and balance that against all the other elements that you pointed out, whether there's a biomarker, whether you can actually move, you can design a clinical trial to show a change, to do all the things in research that we need to do. Yeah.

Dr. Emma James

I mean, fundamentally, you need a patient champion for that voice within the company who is arguing for that. But I do think there is a move, especially within the gene therapy world, to the much, much earlier engagement with the patient community, given the stakes.

Dr. Emma James

I think one of the things companies often balance is how early is too early to engage, because we look at a lot of different therapy areas. And of course, many of these therapy areas have no therapeutic options. And so the moments that you start to engage with the patient community, you raise that hope. And so I think you have to engage very carefully. I think having some one or two very strong patient advocacy organizations who sort of understand what drug development is and the things that we're balancing can be a huge, huge advantage so that you can engage in that early way and sort of say, we haven't got a programme. We're hoping to develop a programme. We want to learn about your disease and your population and that lived experience before you then go out to the wider community. I think once you have even signs that you think that you have a development candidate ready, especially in these kinds of disorders, it's really important to then not only just get feedback from the patient advocacy organizations, but do some kind of research with the parents or the people who are going to be involved, whether that's qualitative research, whether that's quantitative research, whether that's a mixed methods approach, just to solicit feedback on what endpoints do you want to see in a clinical trial? What is meaningful to you? Because that often is different from what the clinicians say. And it certainly is often different to what the regulators say. And I think also the other thing that is incredibly powerful is, again, having that discussion with the potential participants or the community that would be participating in that clinical trial about what they perceive the acceptable risk and benefit profile to be. I do think we need to be moving more to a world

Dr. Emma James

where that feedback is systematically included in submissions to regulators and IRBs. I think we are moving there, but there is still some discrepancy. But increasingly over the past few years, I've certainly seen those kinds of bodies asking specifically. what you know what have you done to find out what the patients think and do they think this this risk benefit is tolerant but tolerable because if they do then okay um and and then you know i know sometimes talking about them internally the company you know we do love to have patient speakers to come in um and i see some things online sometimes about i think people are feeling perhaps like it's a cheap move from industry but i really don't think it it's taken that way internally people really really welcome having patient advocacy groups or even a patient representative come and actually share what it is what to live with that disease and what they need from it so that the different people whether it's the scientists you know the legal you know whoever it is all across the company who aren't necessarily involved in the day-to-day design all really understanding what it is that you're trying to achieve

Rafael Escandon

Yeah, I completely agree with you there. More exposure is better. I want to do a couple of things here. I want to get to the one question that's come in so far, which asks, why does receipt of gene therapy often preclude subsequent enrollment in future trials? That's really related to the fact that what we've seen, at least traditionally, I think it's changing a little bit, but receipt of a gene therapy or genetic intervention because they often have such a long and unknown tail on both durability of efficacy and or late to emerge safety issues. Other companies or other interventions that are being developed have at least frequently excluded patients who've received a prior gene therapy in their intervention because of the fear that perhaps untoward adverse effects mostly would impact their intervention, their research intervention. Similarly, if there is a long tail on durability of some efficacy, that may also introduce variability into there. So that's the short answer to that question. But Emma, I wanna pick up on something that you, a couple of things that you said, because they've been important throughout. throughout this week.

Rafael Escandon

But I want to also keep us focused on our development timeline here. So let's talk about first in human dose selection. I'm going to start with John because I think this is where the rubber meets the road in terms of a nexus of let's imagine a situation not difficult to imagine because it exists so frequently. no standard of a condition that has no it's rare it has no standard of care it's a severe condition that is that either

Dr. John Lantos

disability

Rafael Escandon

accrue significant disability accrues very quickly or or even the worst outcome death happens so in a context like that let's talk about the kinds of of ethical principles we need to think about when selecting that first dose, knowing that it's a one-time opportunity.

Rafael Escandon

Let's imagine you, John, as a physician investigator at this point and thinking about talking to a family, to parents about participating in a trial like that.

Dr. John Lantos

Well, I think the underlying conceptual problem here is that we all have in our minds the phase one, phase two, phase three model as the ideal way to begin to understand risks and toxicities of drugs. And in that model, you have a large group of patients and you can select a small subset of them and you can do dose escalation just looking for toxicity with the mythic belief that neither investigators nor research participants hold that the goal of such studies has nothing to do with benefit for the patient but is only and purely to understand the toxicity of the drug I don't think that was ever quite true even for drug trials for cancer. If you ask people, they all think they're enrolling in the study because they have a hope of benefit. It's certainly not true for gene therapies where people are desperate for treatment. And so the whole

Dr. John Lantos

model that we have in our head that we're going to somehow be able to quantify toxicity before we start thinking about benefit is essentially irrelevant or obsolete in this space so then the question becomes what other basis is there to pick a dose that you think is going to be safe enough and have the potential for actual benefit in other words it's sort of a phase two three if we're going to use that obsolete model And the only basis for those would be either prior animal work, which has known shortcomings, or biologic plausibility. And it's largely a guess, I think, with an attempt to minimize potential risk and hope for some benefit. I mean, the slides you showed on Zolgensma, I think, illustrate how that might work. At the lowest dose, it didn't help. At the higher doses, it did. But it may have been you needed a third or fourth level. They just happened to have lucked out on the second.

Rafael Escandon

Yeah, yeah. Again, I view that as largely as, and I think many would view that as a real success in terms of sort of minimizing the number in the obsolete models. And I agree with everything you said. In the obsolete model, They minimize the number of participants who received a dose that didn't work. And that's a real, I think that's an underappreciated element. Now, Emma, in practice, how easy is that to do? I

Dr. Emma James

mean, it's just as John said, it's hard to do. So we spend a lot of time, if I say we, It's people who are far smarter on this kind of stuff than me. It's not me. But we spent a lot of time trying to figure out what, or not even figure out, trying to predict what doses are going to be efficacious. So one never starts a gene therapy trial with a dose that is known to be sub-therapeutic because of the fact that you can't redose. And that's one of the things that's really very different between traditional chronically administered therapeutics and gene therapies is the traditional dose finding trials are not possible. So that goes back to the slide that Rafa presented earlier where you do these trials in a very small number of patients and you stagger the doses and you do one patient and you see what happens and then you do another patient and you see what happens. And that's part of the reason you want endpoints that you can measure quickly And biomarkers become very helpful. So again, you can see if you're going to be having the kind of effect that you want.

Dr. Emma James

The way we do it is really that we look at the animal models. And I mentioned earlier that we need robust animal models of the disease where we can determine the optimal efficacy and the safety within the animal models. small models, small animals, so rats or mice. Once we've determined that minimally efficacious, or minimally and maximally efficacious dose, or balancing the maximal with the safety, we then test the gene therapy typically in non-human primates. The difference with the non-human primates is that they are not a model. So they are non-human primates, they are a wild type, they don't have the disease. which means you can't test efficacy in the NHPs. You are just testing safety. So then you use the NHPs to determine what is what you call the no observed adverse event level. It's the highest level you can go to without causing toxicity in those monkeys. And then based off the efficacy and the safety that you see across the mice or the rats and the monkeys, you then have a range of doses that you believe to be both safe and effective.

Dr. Emma James

And then we have to figure out how you translate that into humans. And that really, again, varies based off the disease that you're targeting and the route of administration. So for example, if it's an intravenous administered drug that's delivered according to weight, then you'll be trying to extrapolate what that dose is in mice and monkeys and how that differs based off the human blood volume. And similarly, if you're doing something for the brain, for example, if it's administered into the brain ventricles, then you do a calculation based off the CSF volume. in the mice to the monkeys to the humans to extrapolate again how how you're making the the exact same doses from those animals so again when you get to humans you can have something that is safe and at least minimally effective so that everyone has that prospect of benefit to john's point that's the that's the science behind it but we've we've heard you know, many times that, you know, mice are not humans. Monkeys are not humans either. They're a bit closer, but it does really take until being into humans to really be able to tell, you know, are you getting the kind of effects that you need?

Rafael Escandon

yeah and i think it's it's a great point um and i i really i appreciate that description of of the how you get there we've spoken many times in the past emma about what a difficult decision that is to even to find that first to even propose that first dose for first in humans with a gene therapy you want it to work if it's going to work you want to expose as few patients as possible to uh to a sub-therapeutic dose maybe you get lucky Maybe you don't. And maybe on that, not to be glib, I'm not intending to be glib, but I do want to pick up on a thread that has come up a couple times, especially yesterday, which I think was, there were great presentations by Rachel McGinn in particular from NeuroGene where there was continued dose escalation, a continued search for maximal uh safety and efficacy and and

Rafael Escandon

some maybe some false confidence that was given by animal models and translational research uh that that then uh demonstrated that you know for whatever reason um there were some untoward effects and and some death a death in their trial there have been deaths in other gene therapy trials at high doses and so when we think about those consequences, coming back to a consent question and under making sure that

Rafael Escandon

obviously the potential participants and their parents have a true understanding that number one, this is research, this remains being, this remains research. And number two, that there is this possible terrible, even almost unthinkable untoward consequences. John, what do you think about what you've heard this week about consent, what we've heard, what the traditional tenants of consent are, and are those obsolete in this context too, in this context of rarity, of permanence, of perhaps therapeutic misconception and maybe a little bit too much hope?

Dr. John Lantos

I think one of the things that's unique about researching rare diseases is the degree of engagement of the research participants and their families. So informed consent as a model, it was developed and was based on the idea of sort of stranger medicine coming, you know, doctor doesn't know the patient, patient doesn't know the doctor, it's an acute illness, whether it's heart disease or cancer. And you're supposed to quickly describe risks and benefits in a way that somebody can make a quick decision about whether to undergo a potentially lifesaving intervention. The situation with rare diseases is fundamentally different in a way that I think is really ethically relevant here, to the extent that you have a highly engaged, highly informed patient and family community. the idea of consent as this one-time process and discussion is as obsolete as the phase one, phase two, phase three trials. Families become collaborators at every stage of the research process. They still face the same

Dr. John Lantos

difficult decision about whether to consent. In rare diseases, it's usually parents consenting on behalf of their children, but to sign their child up to be one of the first to undergo this. We're going to talk a little bit about who goes first if we have time, but that tension plays out in discussions about whether the first patient should be an adult who can understand and consent for themselves. but who because they're an adult likely doesn't have the most severe disease or they wouldn't still be alive. So do you go for the person who can give more valid consent but is less likely to benefit or do you go to the person who's more likely to benefit but because they're young and therefore more likely to benefit, they can't possibly consent on their own behalf?

Rafael Escandon

yeah it does bring in questions right the fundamental elements that you taught me a long time ago which were which were really you know what is the zone of parental discretion what uh how does the harm principle apply all these really just anything about surrogate decision making right parental authority in general and this is we are the pgtme so pretty focused obviously on pediatrics and and so this is uh It just it complicates things. I want to and I really want this thread to continue, but I think it can continue in a couple of ways. I do want to get to two more things that I think are really important. And but I want to answer. It looks like a couple of questions in the in the in the chat here. One of them is you've discussed how companies could best reach out to patients, but what about the opposite, especially when families or patients fundraise for their own trials and or approach researchers directly? How should those requests be handled? That's a really good question. And I think that will differ condition to condition and company to company. And I think, I don't know, Emma, if you have any thoughts about, that's a hard one.

Rafael Escandon

And I think don't, don't hesitate to approach a company i would say i would say that off the top and then in terms of the kinds of uh research or the fundraising opportunities things get a little bit a little bit more complicated um that way and and advocacy groups for example or groups conducting their own trials i would advise folks to um to get a lot to have some discussions and get a lot of advice before you start to spend money on, even if it's a natural history or a registry collection, there are some things that you can do that will be, I think, sort of higher value in terms of what information you collect, how you collected the methods. So hard question there, good question though. Short answer is I would recommend just not hesitating to reach out to a company. That's the best thing you can do.

Dr. Emma James

And some companies, you know, do list sort of areas of research focus on their website. And certainly, you know, I guess pay attention to what the company is already researching because, you know, it's likely if they're going to be interested in it, it's going to be something like to be interested in something that, you know, is already in their wheelhouse.

Rafael Escandon

Yeah, maximize the synergy, right? I think that's a really good point. I realize that's not super specific. Then the other question, John, I think you addressed largely, which is related to the sufficiency of the informed consent process when it comes to pediatric gene therapy research. Parents want or expect the best outcomes. I think want, absolutely. I think the expectation part is the real nuance that we have to do our best at getting to. in the end expecting uh uh the best outcome the tension between that and research is very significant right equipoise i hate to use the e word but like equipoise is what research medical research is built upon which is really uh true a state of debate or a state of uncertainty between um the possible outcomes or the possible the possible effect of an intervention you're studying it for those reasons so the expectation of of um of efficacy i think is one that is um pretty there's a lot of tension with that so i don't know john if you have anything to add um based on what you said to that

Dr. John Lantos

Just quickly, informed consent is necessary but not sufficient, as the question suggests. And the reason has to do with this concept that you briefly mentioned before, the zone of parental discretion. So in clinical care, as opposed to research, there are certain decisions that we turn to parents to help us make. And there are certain decisions that we say are not in that zone of parental discretion. If a treatment is clearly in the child's best interest, then health care professionals have an ethical obligation to see that it's provided whether the parents want it or not. So we are quite paternalistic or parentalistic in overriding parents' requests on the basis of our assessment of what's best for the child. In research, the comparable concept is there are certain protocols that we think are too risky and therefore don't get IRB approval. then even with consent,

Dr. John Lantos

that's not enough. It also has to meet the standards for what counts as acceptable research before we even get to the stage of asking for parental consent. And that's usually, as the question suggests, about having realistic expectations that sort of these are therapies that have never been used before. We don't know the risks. based on what we've learned so far in this space, we think there are going to be risks that we haven't anticipated and people are gonna die as a result. And parents need to understand that and defer to a certain amount of the expertise of the scientists. There's all this stuff about citizen science, but in my mind, I always think, do we want like citizen engineering? Like people just go like, I know how to build a bridge. No. We actually want people with the skills to build that bridge. We actually want people who understand the science and the risks of these new therapies to be the ones who are shaping the questions that we then put to parents.

Rafael Escandon

Yeah, no, thank you. Emma, any comments there?

Dr. Emma James

Yeah, I was just going to say, I guess, you know, and I am absolutely, you know, my team will talk about how much I... harp on about the importance of informed consent, but how difficult it is to actually make consent actually informed, especially in these very, very complex disorders and treatment modalities. I think one of the challenges is we've sort of moved into this era where in the spirit of making sure that families have all of the information, we are forced into putting all of this information into informed consent forms. And then you end up with a 40 page document that nobody can read or understand, including me. And, you know, and then there to have that sort of, I guess, that that challenge just at the IRB level, which is well intentioned, but perhaps means we end up not getting the result we need.

Dr. Emma James

And we can provide other additional supplementary materials to help. with that informed consent form, but different hospitals have different policies on acceptable use of those kinds of materials. And so I then wonder about the, I guess the ethics ultimately of, you might have one participant in a trial at one site having a very different understanding and experience of that than a participant at another site. So even how do we make that informed consent process more accessible and they're more equitable too.

Rafael Escandon

Yeah, it's dynamic. I think that's true. And it goes back to an old, you know, part of the fundamental rationale for individual ethics committees at individual institutions is this concept that all ethics are local, right? That individual IRB is supposed to be able to represent the local population appropriately. And I think as you point out, that seems to be a very static target. And I wanna bring this into a thread that

Rafael Escandon

I think we should pick up on, which is, you know, if, for example, something, there's a development of an adverse event in a gene therapy clinical trial, and that needs to be, that the consent, form the consent process needs to be updated to include those risks that were not previously known those tend to be the touch points with the irb whereas you know one of the stakeholders that i haven't mentioned here particularly in early development are data safety monitoring committees and data safety monitoring boards and i'm on a couple um because i'm an independent person now i don't work for for biopharmaceutical companies but um they're actually charged a bit more with looking at the emerging safety information and then making some recommendations, but they're not the IRB either. So tying together, again, to me, it just brings in this concept that the informed consent is a dynamic process that never ends, right? It can't. And especially for these interventions and when you have now a decade or more of

Rafael Escandon

commitment to a trial or to this intervention, I think that just makes things very different. And I think from a parent's perspective, from the participant's perspective, who's maybe a child when they got it, but they develop into a mature minor and then an adult, after having received it, they're still participating. And so it's a fascinating situation that we haven't really encountered. It's more like a solid organ transplant to me.

Dr. Emma James

Yeah, I mean, we could absolutely go down a rabbit hole on this, but it's funny even talking about, you just mentioned like it never goes away. And yet we say that people can withdraw consent if they wish. You can withdraw consent to be studied. You can't withdraw consent for that study, for that procedure because you've already had it and you can't take it away. So withdrawal of consent isn't truly an option. And then back to your point about you have parents consenting for children and then they actually don't really have the ability they don't have the free will to then be able to consent independently for themselves when they become adults it's it's definitely a challenge i'm sure john has more to say on that than i do

Dr. John Lantos

i mean it's another example of the way we're trying to shoehorn a very different kind of research into a framework that was developed for something uh completely different i mean if you think about dsmb's in randomized control trials, the idea is you're doing an intervention at time zero that may go on for a year. You're giving a cancer chemotherapy, you're giving a cardiac drug, you're giving postmenopausal hormones, whatever. And you don't want either the investigators or the research participants to know what they're getting, but you want somebody able to look at the data in a blinded way. That makes sense in that model. It makes no sense when you're doing N of one or N of five studies where there's no control group and nobody can possibly be blinded. It's

Dr. John Lantos

using the wrong tool to ensure safety in an ongoing clinical process. The right tool, it seems to me, is every bit of information from patient one needs to be available to both investigators and future participants in order to make informed decision. It blows the idea of blinding out of the water but these aren't randomized trials

Rafael Escandon

so

Dr. John Lantos

we're just it's like we need a saw but the only tool we have is a hammer so we're pounding away and can't figure out why nothing's cutting

Rafael Escandon

it's a it's a great point and you've led into something i really wanted to continue in today's discussion that rachel mcminn uh mentioned yesterday and it was just in the context of um of emerging clinical information and what happened in their trial and how she took on, and she and her company took on, I think a very, as she described it yesterday, I thought it was a very admirable and seemed like it was a fairly unique set of efforts to try and understand the prevalence of the very unusual and seemed very rare adverse event that happened in in their gene therapy trial. And through examination of various, you know, sometimes not so accessible databases, they found that this wasn't a unique event to their gene therapy trial. And so she said that she's taken on this effort to reached out to lots of different companies, which to me was courageous and kind of somewhat unheard of. And I think this comes back to a poster that myself and a few other members of the PGTME had at the ASGCT just this past spring, which was, there seems to be a need or there ought to be a way to be able to do what you just described, John, is that all...

Rafael Escandon

every company developing an AAV gene therapy, and let's say it's a specific serotype of, let's say it's an AAV9, they're all stakeholders in the entire continuum of everyone doing that, regardless of what the target indications are, right? And so there isn't currently a way for those folks to share emerging information for lots of reasons.

Rafael Escandon

I think, personally, I think the ethics around that, I feel like I could make a strong ethical argument about why that should be. And it seems like the counter arguments against that are mostly technical and IP related, but also pragmatic. So I don't know, Emma, have any thoughts about the practicalities of being able to do something like that, to share information, even if it's preliminary? This is what we know now across you know, all developers of AAV9s, if you saw something? So,

Dr. Emma James

so basically just to go back to something else you said, so there's actually a really nice example from the DMD community of, I think it was Pfizer, Solid and Sarepta. They each saw deaths in their programs and they via, a handful of external clinicians, essentially formed this little consortium to share data and figure out what was going on across their different products to determine how do we move forward. And they actually wrote that up as a publication. It would have been like Carsten Bonneman and Francesco Montoni, if people want to look it up. But I do think there is a move towards companies being in the same place, trying to work more collaboratively that just a decade ago, we just didn't see. In terms of the sharing of data, I

Dr. Emma James

mean, yes, I completely agree. We need to share data. And, you know, being on, I guess, the receiving end of being a developer and seeing something happen in someone else's program and not knowing what that means for my own program and how I adapt my own program to be able to ensure safety there is incredibly frustrating. You know, and we all know that we end up on, you know, listening to the underground whispers. of bits of information you can glean to try and figure out, is there some catastrophic class effect that we actually need to be addressing very, very quickly? Or is it something that is very, very specific to that product? I think some of the challenges, if you're on the company side, are likely to be fiercely, often you just don't know. so you know you you and often you know it's something that's going on at a site so you don't necessarily actually have all of the information in real time you're waiting for that information to come in yourself and the um and the investigation will be going on at the site so there is a sort of a delay that comes in on that front um and and you know you you you want to be able to go out with a story of there's this going on and this you know we had a safety event,

Dr. Emma James

we have some idea what it is, and these are gonna be the next steps. This is just causing alarm, I suppose, of something happened and we just don't know what it is. And I realized people on the receiving end of that will say, well, we want to know even if you don't know anything. But I think that's what sort of companies are trying to deal with is having information that's actually meaningful to share with people so that you don't cause alarm across, you know, across the whole community that is potentially unnecessary. And then, you know, I think we talked on the panel the other day, there are challenges for, especially for public companies where you have to do a SEC filing before you can do anything else. It has to, you know, you are required. to disclose that to the market before you can disclose it anywhere else. And so there are just things that have to happen first. Now, is that right? Not necessarily. That's

Rafael Escandon

a practicality.

Dr. Emma James

Is it the truth? Is it what happens? Yes. And so, again, companies will be trying to figure out, again, how do they time making sure that you do that public disclosure to the SEC, along with then making sure everybody else is aware at the same time.

Rafael Escandon

Yeah, no, it's a... Again, tension, as you point out. A couple more questions in, and we are unfortunately running short on time. I feel like we could go for another hour or two, but I just want to get to Jordana's comment, which is very well. I think we discussed this a little bit earlier this week, Jordana, and just in terms of her suggestion is to have parents and patient communities involved with the lived experience, well embedded within those that are designing protocols. I think everyone has that good intention, whether there's someone who actually has the condition that's an employee of the company. I think that can take some many forms, but I think your advice is well taken. And then Kara Weissman has actually the point that I did not serve. She's not responding to a question for me, but she really serves up. I think the last point that I wanted this group to look at was kind of what happens when a

Rafael Escandon

company fails or when a company decides to, not take a a gene therapy these permanent interventions for better for worse uh any further forward and so what's the what's the sort of obligation what maybe what's the future state with which how because we've seen many examples of companies going down and then those who've received this these permanent interventions sort of throwing up their hands and not knowing what to do some companies i think uh keep the lights on you know dimly but but give good advice on how to follow up, but others just turn the lights out. So John, what's our ethical, what's the ethical sort of pie in the sky position on that? And how does that intertwine with sort of the clinician's duty to the patient as well?

Dr. John Lantos

It's the tension between clinician's duties, which are fairly well established in both ethics and law. I mean, we can't abandon patients. We can dismiss patients from our practices, but we have obligations to find another provider and to provide them with information that will enable them to provide seamless and competent care based on what we know of the patient's history and medical problems. It seems like it would be a great standard to apply to corporations, but uh there are no comparable traditions or laws um and therefore

Rafael Escandon

yeah go ahead i mean i think i was going to say i was going to kick it to emma and say yeah yeah go ahead how do you plan for that

Dr. Emma James

i mean i think it's difficult to plan for right um i you know you you always have the have the intention you we we get asked in in documents with regulators and and irbs etc like what you know what i how will you maintain this? And the answer always is, we are committed to the programme and we've committed to our patients and we will, if we can't continue it, we will do our best to find a partner who will take the programme on.

Dr. Emma James

And I think that's, I mean, that's ultimately it, is you try to find that partner who can continue to do it if the company cannot continue. I think I don't have the experience to say, but I mean, if a company ultimately runs out of money and no partner has been willing to take it on, I don't really know what happens. So I think that I think that is a that is something that I think we we as a field probably need to. need to understand there are certainly examples where you know programs have been taken back even by patient advocacy organizations and they have moved them forward um but that can be a huge undertaking i mean you know we all know how complex and costly these these trials are so if you already have multiple patients enrolled um to have that taken over by a foundation or a patient advocacy group is is certainly not a small undertaking but i think it is something that we should really start to try and understand and move towards having having frameworks if that happens

Rafael Escandon

yeah

Dr. John Lantos

it's it's not just companies either i mean academic researchers who are doing their research with federal grants have the same problem the ethical obligations of a researcher are not the same as the ethical obligations of a clinician and

Rafael Escandon

right

Dr. John Lantos

the reasons we have different systems of regulation but the idea is the researchers enrolling you in a trial and they have no fiduciary obligation to your health they have an obligation if anything to the good science and if their grant runs out it's like a company going broke

Rafael Escandon

yes yes exactly well maybe that's uh two things from that uh we'll bring aiden in um as well, but two sort of final thoughts there. Number one, maybe that is an area that the PGTME can look at in the future and maybe make some recommendations on that contingency, right? Because it's not theoretical, it's real. And so maybe we can take that up in our 2026 goals. The second thing is maybe Andrew Lowe tomorrow has some thoughts about how companies should when when making the calculation about um about uh gene therapies and rare diseases and and starting companies and being able to fund programs like this uh maybe there's a there's some thoughts to um how to how to provide for this contingent this that unfortunate contingency um if a company or or a research program goes down all right well i just want to thank both of you john and emma we didn't get to half the things well we got to most of the things in some respect or another but your thoughts and engagement is it has just been fantastic and i really appreciate your efforts here working with me on this um on today and aiden always

Dr. John Lantos

a pleasure

Ayden Eilmus

Yeah, I'll just echo what Raphael said, and I'm so sorry to have to cut the conversation short. Like was mentioned earlier, I'm sure we could go on for a long time. But thank you all for such a fantastic and open dialogue. And thank you to all of our attendees as well for your thoughtful questions. Raphael, I appreciate the plug for tomorrow's session, the final day of this year's lunchtime lecture series. A link for the registration has been put in the chat. That will be a talk by Andrew Lo, Improving Patient Access for Gene and Cell Therapies, a Financial Engineering Perspective. So please join us for that. And just on behalf of all of PGTME, thank you to everyone who's attended and participated and helped put today's session together. And have a great rest of your day. Hope to see you all tomorrow. Thank you so much.