Welcome back to Research Ethics Reimagined.
Dan McLean:I'm your host, Dan McLean.
Catherine Batsford:And I'm your cohost, Catherine Batsford. Today we are joined by a leading expert in the intersection of law, medicine, and research ethics who's working to shape the national standards for how we conduct medical science. Holly Fernandez Lynch is the Associate Professor of Medical Ethics at the University of Pennsylvania's Perelman School of Medicine. Holly's work focuses on clinical research ethics, institutional review board quality, and access to investigational medicines and FDA pharmaceutical policy, especially related to early approval pathways and post market study requirements. She is a former board member of PRIM&R and figure in the research oversight community.
Catherine Batsford:Her influence extends deep into federal policy. She served as a member of SACHARP, the secretary's advisory committee of human research protections, which provide guidance to the U. S. Department of Health and Human Services. She is also co founder and co chair of ARIO, which is an ongoing collaborative effort to understand and evaluate and improve IRB quality and effectiveness.
Catherine Batsford:Holly has testified before Congress and authored a wide range of reports, including those which explore the promise and perils of FDA's new plausible mechanism pathway, which is what we'll focus on during our episode. Holly brings a vital perspective to some of the most pressing questions in scientific research today. Holly, thanks again for being here.
Holly Fernandez Lynch, JD, MBe:I'm so glad to be with you.
Dan McLean:We'd like to jump right in, Holly, and just take a second to explore how you got interested in this field and began your focus on this item that we're going to explore, the promise and the perils of FDA's new plausible mechanism pathway. But more specifically, how did it get you where you are and how did you get involved in this field of bioethics?
Holly Fernandez Lynch, JD, MBe:Well, we could go really far back in which I disclosed to the PRIM&R community that when was a freshman in college, I started in a math class that was the next level beyond what I had taken in high school. I felt like I missed a few steps along the way. I had visions of failing out of college. And I went running to my advisor and said, Get me out of this math class. And so she's going through the schedule and says, How about intro to biomedical ethics?
Holly Fernandez Lynch, JD, MBe:And I said, Is it not the math class? Great. Sure. Intro to biomedical ethics it is. And I really fell in love with that class.
Holly Fernandez Lynch, JD, MBe:So it was totally serendipitous. You know, I had been interested in kind of like science and medicine and health, but bioethics was a newer field still at that time. Now there are like high school bioethics programs. I didn't have exposure to bioethics in high school. I don't think I had even heard of it until it was mentioned to me in that class.
Holly Fernandez Lynch, JD, MBe:So it was also the time where there were ads in our school newspaper of people looking to buy our eggs, you know, lots of interesting bioethics challenges at that time. And so I really fell in love with the field and I knew that I was interested in the policy angles, which is why I pursued law school. And the way in which I thought I would most be able to marry my interest in law and bioethics was to focus on research and such a heavily regulated area. So I started right after law school in a law firm in their FDA practice group. So I was learning more about how clinical trials are run and how sponsors think about those things and how pharmaceutical companies and biotech companies think about those things.
Holly Fernandez Lynch, JD, MBe:I had the chance to then work at the Division of AIDS, completely different perspective, right? Like how does a government sponsor think about its responsibilities? At the Division of AIDS, of course, we were doing a lot of global research, raised interesting ethical questions. And so that was kind of how it started. And today my work focuses, as you mentioned, Katherine, on all things related to FDA drug and biotech policy.
Holly Fernandez Lynch, JD, MBe:And so this plausible mechanism pathway is right up my alley because I spend a lot of time thinking about how much evidence is enough evidence before we allow a product on the market, but also thinking about the ways in which our typical approaches might not be feasible for rare disease and certainly not for ultra rare disease. And that's exactly what this pathway is intended to address, right? For these N of one or N of few diseases, we have the scientific capacity now to treat them, but the regulatory approach needs to catch up.
Dan McLean:So with plausible mechanism pathways, which is kind of a it's hard to get what those words actually mean. So what does it actually what does it what does it mean? What are the promises? What are the concerns? It sounds like that there are are both.
Dan McLean:And so if you could just break that down of what it actually means, what what problem is the FDA trying to solve, and what concerns may be created as they attempt to solve that problem.
Holly Fernandez Lynch, JD, MBe:Yeah. Okay. So what does plausible mechanism mean? I should also emphasize I am a lawyer. I am not a doctor.
Holly Fernandez Lynch, JD, MBe:I'm not a clinical trialist. I'm not a geneticist or a statistician or any of those things. I always joke, missed that day of law school relevant to so many of the things that I work on now. But I collaborate all the time with people who do have those credentials. And so sometimes you can understand a particular disease pathway in a mechanistic way, meaning we know that this disorder is caused by this gene or this biological process.
Holly Fernandez Lynch, JD, MBe:And therefore, if we can intervene on that biological process, we would expect that the negative outcomes won't happen. Right? So there is a plausible mechanism. If we intervene on this, it ought to work. Now, sometimes plausibility doesn't pan out, right?
Holly Fernandez Lynch, JD, MBe:Like we think, Oh, if we make this adjustment, it's going to lead to a positive result. And then you do a clinical trial and it doesn't actually lead to the expected results. So I can give an example of this. In Duchenne muscular dystrophy, which is a genetic disorder that results in inability to make a particular substance called dystrophin, which is related to muscle function, you would expect, Oh, well, if I can get the body to make dystrophin, then I will be able to avoid those negative results. And there is a company called Sarepta that has developed several products to treat the chain.
Holly Fernandez Lynch, JD, MBe:They've had a lot of difficulty meeting their clinical endpoints in their studies. And one theory about why is that they can't get the body to produce enough dystrophin. Their intervention lead to improved dystrophin production, but maybe it's not enough to hit the threshold to have the biological effect that you want to have. So anyway, that was a long winded answer, but that's what we mean when we talk about plausible mechanism. We have a good biologic reason to think this thing is going to work, but we're not sure.
Holly Fernandez Lynch, JD, MBe:So for a common disease, we would say, all right, this is our plausible mechanism and we're gonna study it in an optimally designed trial, right? A randomized, double blind, controlled study. If you have one patient or two patients or three patients that have that particular disorder, that particular genetic disorder, or that particular variant on the gene, there's just no conceivable way you could do a typical clinical trial. And so what typically would happen is for every change you make to a drug product, you would need a new investigational new drug application or biologics submission to do the trial, right? But for these individualized therapeutics, the platform is the same regardless of the specific variant that a particular patient has.
Holly Fernandez Lynch, JD, MBe:And so if you had to go back and do all the animal studies and all the manufacturing submissions and all of that for every single variant, you could never get that off the ground, right? I mean,
Catherine Batsford:how expensive would that be?
Holly Fernandez Lynch, JD, MBe:It would be incredibly expensive. It would be incredibly time consuming and you just couldn't conceivably make that work. And I want to just take a step back to talk about the patients here, right?
Dan McLean:So
Holly Fernandez Lynch, JD, MBe:there's a few different technologies that can be used, right? One is called an antisense oligonucleotide, which you might see with the acronym ASO. The very first individualized therapeutic was an ASO that was developed for a little girl named Mila in 2018 in Boston. And the way the ASOs work is that they influence how the mRNA is reading the genetic code and basically prevents the incorrect reading. So that's one type of individualized therapeutic.
Holly Fernandez Lynch, JD, MBe:You individualize it by changing the nucleotide sequence based on the particular that that person has. But the ASO backbone is the same. It's just that sequence that's individualized for each patient. More recently, you might've seen in the news a very adorable baby named KJ who was treated at CHOP. I met Penn, CHOP is right next door and we collaborate a lot.
Holly Fernandez Lynch, JD, MBe:So KJ was born with a urea cycle disorder that was caused by a variant in a particular gene. And so his team developed a gene editor. It's called a base editor. And unlike the ASOs, which don't actually change the underlying gene, the gene editors do, right? And they can make this pinpoint change to the sequence.
Holly Fernandez Lynch, JD, MBe:We learn about the high school biology, right? They can make a T and A or whatever the appropriate sequence is. But similar to the ASOs, these are a type of, they're called a platform technology. So what the gene editor, this particular gene editor for KJ is it's a lipid nanoparticle, just think of it like a little ball, and that is transporting the payload. And inside the lipid nanoparticle is a guide RNA that takes it to the right part of the gene where you need to make that switch and an mRNA base editor, which can make that pinpoint change.
Holly Fernandez Lynch, JD, MBe:So for each variant, all you have to change is the guide RNA. But the ball, the lipid nanoparticle, right? And the mRNA, those stay the same. So you could just swap out the guide RNA. So these are platform technologies, right?
Holly Fernandez Lynch, JD, MBe:But if you think about how FDA was regulating these things, every change to the guide RNA or every change to the nucleotide sequence would be a brand new drug that you'd have to do all the studies all over again. You'd have to do all the manufacturing studies all over again for every single patient. And so that was, as I said, just like not a plausible thing to do. And so FDA for a long time has recognized that this is going to be a challenge ever since Mila was treated. So we saw that FDA leadership back in 2018 or 2019 was publishing questions about like how much evidence is enough for us to allow one patient to be treated with a novel intervention?
Holly Fernandez Lynch, JD, MBe:And how could we address some of these commercialization challenges if we're talking about one patient at a time? They ended up publishing three guidance documents for N of one interventions, but the FDA can issue guidance documents to different audiences, right? So they can say, if you look at these, they'll say guidance for industry or they'll say guidance for investigators, right? So these were three guidances that were for sponsor investigators. Like the academic clinicians who work at these medical centers who are just trying to figure out how to take care of their patients and are not pharma company or a biotech company that could actually weigh in and figure this out and commercialize it.
Holly Fernandez Lynch, JD, MBe:So those guidance documents basically talked about how do you get informed consent around these things? What would manufacturing look like? They were all directed to literally, you're treating one patient, you're treating They two explicitly said, this is not for industry. This is directed to these academic clinicians. But they were starting to think more on this kind of platform technology approach.
Holly Fernandez Lynch, JD, MBe:So how was it that baby KJ was able to be treated? That was, if you look at this document, the journal article in which FDA articulates this plausible mechanism pathway, they point to various features of KJ's case. And they say, Look, here was a circumstance where we knew exactly what the molecular cause was of this baby's disorder. We, the royal we, the scientists had developed a targeted product that they knew was going to go right after that biological alteration. We knew what was going to happen with the natural history of this disorder, right?
Holly Fernandez Lynch, JD, MBe:If you have urea cycle disorder, the ammonia builds up in your blood because you can't break down proteins and you need a liver transplant, but newborn babies can't get a liver transplant. You have to wait. It's death or liver transplant are the outcomes. So we know what's going to happen on the natural history of the disease. And then they were able to confirm what's called target engagement.
Holly Fernandez Lynch, JD, MBe:So here at AJ's disorder, they needed to edit the liver cells to change how it was producing this protein. And you're not gonna do a liver biopsy on an infant, but they did on the animal model, they were able to determine that a sufficient number of liver cells actually had their genes changed to produce the proper protein, right? So target engagement was confirmed and then clinical improvement was demonstrated, right? Baby KJ was able to start having a more protein rich diet. He was able to stop taking some of the medicines.
Holly Fernandez Lynch, JD, MBe:I think they're called nitrogen scavengers, which sounds very cool, right? So he was able to reduce those medicines and none of that, according to the natural history, would have been expected if the genetic editing if the gene editor didn't work. So these were five factors that came up in KJ's case that FDA said, All right, those are the five factors that we're going to look for to use this plausible mechanism pathway.
Catherine Batsford:For every case that could come up?
Holly Fernandez Lynch, JD, MBe:All right.
Catherine Batsford:So here's
Holly Fernandez Lynch, JD, MBe:what FDA did. And I jumped around a little bit because how is it that baby KJ was able to be treated this way if we didn't yet have the plausible mechanism pathway? Basically what happened for him was that his team of scientists was meeting regularly with FDA and coming up with all these incredibly novel, innovative regulatory approaches where FDA was just kind of saying, okay, yes, we'll allow that, we'll allow that. So KJ was treated under a single patient expanded access submission, single patient IND. That was actually FDA turned that around in days, less than a week.
Holly Fernandez Lynch, JD, MBe:I can't remember if it was exactly that short, but it was a very rapid turnaround time.
Catherine Batsford:It's astonishing. Now
Holly Fernandez Lynch, JD, MBe:the team had been in conduct.
Dan McLean:Does that situation happen frequently where you can get that permission from the FDA to say, hey. We're just gonna do our own thing on this. Is that okay?
Holly Fernandez Lynch, JD, MBe:Well, everything about what happened with KJ was totally unique. Okay. But the expanded access pathway exists. The stuff that was unique about KJ was that he was getting this individualized gene editor. But the way expanded access works is if you are a patient who could not enroll in a clinical trial because you're not eligible or you couldn't get to the site because it's very far away or a variety of reasons that you couldn't participate in a trial and your doctor thinks that you could benefit from that investigational intervention and that the benefits outweigh the risks and a couple of other criteria are satisfied, including that the company is willing to give you access to their investigational drug, then FDA will authorize expanded The IRB also has to say yes, there's a streamlined pathway to get expanded access.
Holly Fernandez Lynch, JD, MBe:Expanded access comes in different flavors. So you can have a single patient IND, you could have an intermediate sized patient population or a treatment protocol. The bigger ones require more confidence about benefit and about avoiding risk. But on the single patient IND, you don't really need much, right? Just basically have to say this patient has no plausible treatment alternatives that are as good as what we think this investigational intervention will be.
Holly Fernandez Lynch, JD, MBe:So they used a single patient IND for baby KJ, and they want to do this for other other babies. They had developed an approach that the scientists who treated baby KJ published that articulated what FDA had agreed to for them, which was start with gene specific INDs. Urea cycle disorder, I think, has seven or eight genes that cause that disorder. And within a particular gene, you might have variant A, B, C, whatever. Right?
Holly Fernandez Lynch, JD, MBe:So have a have a one IND per gene. But the INDs can rely on information from each other. So you can rely, for example, on the same animal studies. And you could use data from previous patients that didn't have the exact same variant or didn't have the exact same gene, but you're adding them based only on in vivo data, meaning like lab cultures and that kind of thing rather than based on in vitro people. Sorry, I think I actually, I switched that.
Holly Fernandez Lynch, JD, MBe:That's okay. Scratched that, right? In vivo is in the person, in vitro is in a dish, right? So the gist of what FDA had agreed to in this particular instance was an umbrella trial. You say, look, we are interested in studying urea cycle disorders.
Holly Fernandez Lynch, JD, MBe:Here is our gene specific IND number one. We're going to treat baby number one who has this variant on this gene. Oh, along comes baby number two. They also have urea cycle disorder, but it's in a different gene. And so we are going to rely on the information, the manufacturing information, the animal toxicity stuff from that first IND.
Holly Fernandez Lynch, JD, MBe:And we're just going to do a lab test to see that this change to the RNA seems to work, right? Then we're going to be able to treat this nude baby and on and on and on. So urea cycle disorders are not N of one. It's that each variant could maybe only be N of one. So that was the model prior to this plausible mechanism publication, but not very much prior.
Holly Fernandez Lynch, JD, MBe:They had just published that a couple of months ago, but it wasn't formal FDA policy, right? It was like these researchers got FDA to agree to these things and they published it so other researchers could try to get FDA to agree to the same for them. This plausible mechanism pathway is FDA saying, Okay, we get it. We see that there's a scientific development here that we need to adjust our approach to, and here's our proposal for how we're going to go about doing it. And it's really remarkable.
Holly Fernandez Lynch, JD, MBe:A great idea for these truly N of one or N of a couple situations where you would not be able to do anything even close to a randomized controlled study. But like I said, you could have a genetic disorder where you have a bunch of N of one variant, but you put them all together and maybe you could get some commercial interest. And that is what this approach is intended to address, that you can start pooling the variants together so that it's no longer asking a company to come in to sponsor a drug for one person.
Catherine Batsford:Right.
Holly Fernandez Lynch, JD, MBe:You can kind of extrapolate in a way that would make it commercially feasible.
Catherine Batsford:Because what is the cost, honestly? Yeah,
Holly Fernandez Lynch, JD, MBe:they have not disclosed the cost for baby KJ. It wouldn't be as expensive every time. You know how these things go, For the first patient, it's extraordinarily expensive and then you figure out how to do So it would be extremely expensive if you had to do all of those steps for each individual you should be able to kind of build on all of those data approaches that I mentioned. That should dramatically reduce the cost and dramatically reduce the time. I have no idea what the market cost would be if you were able to commercialize one of these things.
Holly Fernandez Lynch, JD, MBe:Because the way that companies typically do that, right, is to argue, look at all of the savings that you would get by avoiding all of the other medical interventions. Just fixing the gene, right? You should be willing to pay a lot. We've seen gene therapies be priced very high outside the end of
Catherine Batsford:one case. And the informed consent on gene therapy is in some ways unique because you can't stop a gene therapy halfway through because there's an effect that's happened. It's essentially you've done it and now you have to watch the person for to see what happens.
Holly Fernandez Lynch, JD, MBe:Yeah, that's right. So some of the other approaches to gene therapy require a viral vector. And if you had previously been exposed to that virus, then you're not candidate for that gene therapy. Sometimes the other thing that comes up is you get one chance at it because if you have received gene therapy A with this viral vector and it doesn't work, but, oh, in two years, here's another gene therapy that seems to be better, but it uses that same viral vector, the first, you've lost your chance. And so look, context that we're talking about here, I mean, I described baby KJ, it was liver transplant or death.
Holly Fernandez Lynch, JD, MBe:It makes sense that people are willing to take pretty substantial risks and they're willing to accept pretty substantial uncertainty in these scenarios, but the risks are real, right? I mean, every time that you're introducing a brand new product into a person for the first time, you don't know exactly what's going to happen. Our animal models are important, but not perfect. And I know from speaking to them that baby KJ's team took that responsibility incredibly seriously. They needed to move quickly, right?
Holly Fernandez Lynch, JD, MBe:Because his case was progressing. I should also say that KJ came along at the right time. So the scientific team had been working on this approach for quite some time. And then it was ready at the same time KJ was born and that he was the first patient that they could try it on. But I know there had also been some questions that his team has received about like, was it KJ?
Holly Fernandez Lynch, JD, MBe:Right? What about my baby who also has a similar disorder? And obviously the goal is eventually to be able to use these technologies to treat all of the people who could benefit from them. But like anything else, as you're beginning this, you gotta figure out how to get it off the ground. So it is a bit of right place, right time.
Dan McLean:So it's basically personalized treatment that will be unique for that individual, but following the same approach or system that's been developed. But each one of those applications is in effect in a one attempt. Is that Yes, generally speaking, that's that's correct.
Holly Fernandez Lynch, JD, MBe:But once you figure out that this base editor works, then all left to figure out is does this guide RNA actually get it to the right part of the gene to make the switch? And then in any gene therapy, again, lawyer talking here, not geneticists, but in any gene therapy, you also worry about what's called off target effects, right? Where you're trying to send it to make a change here, but whoops, it made a change somewhere else. And sometimes those off target effects, you can't tell. And sometimes they could be devastating, right?
Holly Fernandez Lynch, JD, MBe:It's a pretty big deal to get in there and muck around with the genetic code, right? Yeah. It is worth kind of taking a step back to just like let your jaw hang open for a minute and say, Oh my God, they were able to, for this baby who had a genetic disorder, change his gene. So now it works. I mean, it's just incredible when you take a second to think about what they're able to do.
Catherine Batsford:It feels like science fiction of our childhood. Know, you could wave something over someone and fix it.
Dan McLean:We've got, like, two questions at least, but, Katherine, I don't know if there's one that right?
Catherine Batsford:I mean, I think you talked a little bit about individualized therapies, but I think the ethics and justice behind it is that question. When when does the access become affordable for all? Or how do you take this this kind of research and make it human subjects research so that it's for everyone? Are we avoiding other pieces of science that should be addressed that would accomplish more for more people?
Holly Fernandez Lynch, JD, MBe:Yeah. So Mila's mother, Mila actually passed away after she had received her ASO in part because her disorder was such that by the time she got treatment, it was It not was too late. But Mila's mother has her name is Julia Vitarello. She has really taken the baton to say, how do we get from N of one to N of everyone, right? Everyone who could benefit from these interventions.
Holly Fernandez Lynch, JD, MBe:And that's exactly what this umbrella trial design and this plausible mechanism pathway is trying to get to. It would be terribly unjust if we said, okay, we've got to do it all over again. The process has to happen for each individual person because who can do that, right? It's going to be the babies who happen to be treated at CHOP and are in the right place at the right time. And we know that that's not going to be equally accessible to everybody.
Holly Fernandez Lynch, JD, MBe:And so the whole goal of this approach is to make it something that could be commercialized. The other thing you asked, Katherine, about price or cost of all of this, insurance companies are not going to pay for an investigational product. So that's a really important reason why we care about getting to commercialization. One is to develop the product and the other is to make sure that people can actually use it once it's developed. And so this model of saying, here's how we could get it to approval for more than one person should then leave insurance companies to be willing to pay for it, which obviously is a key part of access, equitable access.
Holly Fernandez Lynch, JD, MBe:All I can say for now is that's the goal, but it's not something that we're going to snap our fingers and have it happen overnight. Yeah.
Dan McLean:Well, sounds like that this is an example of the FDA being nimble. Isn't that I mean, that sounds like a good thing Yeah. That they're not saying, wait a second. We have these rules. This all sounds well and good, but you gotta run through the traps and and it's gonna take whatever time it's gonna take, and you have to follow the procedure as written.
Dan McLean:So it sounds like that's not what happened here, which sounds like a positive development, and there's a lot of excitement around it. But it also sounds like that there's some concerns that you've raised in your in your writing that if I got it right, you're concerned that they'll say, okay. This is good for this use, but what's to stop that from broadly expanding in ways that may be unexpected or concerning? Do you want to elaborate on that a little bit?
Holly Fernandez Lynch, JD, MBe:Yes. Okay. So here's a concern that I have about being a bioethicist in general. It's like, all right, here comes Holly to rain on everyone's parade. Here's this great thing and tell us everything that's wrong with it.
Holly Fernandez Lynch, JD, MBe:So I will say again, it is a great thing. It's great that FDA is willing to be flexible about this, but I have a bunch of concerns both about what they've articulated and the way in which they've gone about articulating it. So here are a few of the things that I'm worried about. I went through and shared with you kind of these five defining characteristics that FDA said, Look, this is what worked in KJ's case, and so we're going to use that as a model going forward, right? We know what the disease is.
Holly Fernandez Lynch, JD, MBe:We can target it, right? We know what the natural history is. We can see clinical improvement, right? Those are the things that they're looking for. And they said, this will work pretty well if you couldn't do a randomized controlled trial.
Holly Fernandez Lynch, JD, MBe:What they did not say was, We will only use this if you can't do a randomized And controlled so you want to compare what we're talking about on the plausible mechanism pathway for what would typically be expected, right, is that you run a clinical evaluation to figure out does this thing in fact work. And earlier I gave you an example of a gene therapy that doesn't seem to work for patients. Now, I'm hesitating a bit because the gene therapy for Duchenne has been tremendously controversial, right? It did meet its endpoints in trials. It got approval anyway.
Holly Fernandez Lynch, JD, MBe:It did meet some secondary endpoints. Some people are having that outcome. So take what I'm saying, right, with a grain of salt. It's just that these things don't always work. A plausible mechanism is not a certain mechanism.
Holly Fernandez Lynch, JD, MBe:So when you could do a randomized controlled trial, you should do that. Right? But FDA over the past several decades has had a trend, a very obvious trend toward reducing the level of evidence that's needed for approval. So my concern is let's make sure that this awesome pathway for N of one and N of a few is reserved for that and not used as a way to reduce the evidence about other products that are going to be allowed on the market. Now, in that article that FDA published about the plausible mechanism pathway, they say, Yes, yes, this is awesome for N of one and a few, but it could also be used for more common diseases.
Holly Fernandez Lynch, JD, MBe:So we're like, What does that mean? And the example that they give is a disorder that has 150 different variations on the gene. It's like, okay, but that's exactly what we were talking about. That would be N of one, N of few, right? If there's just a handful of people who have that particular variation.
Holly Fernandez Lynch, JD, MBe:So I don't know what they mean when they say maybe it could be used for common diseases. I'll give you another example. In PKU disorder, phenylketonuria, I'm sure I'm not saying that right. I don't have the word in front of me right now. This other disorder, there's lots of different variants and there are several people who have a particular variant, right?
Holly Fernandez Lynch, JD, MBe:Like maybe a couple thousand people have a particular variant. You could do a randomized controlled trial with that. Our concern is when you have a variant that just one or two or three people have. So drawing the right dividing lines so that we're not giving up evidence that would be really helpful to have, think is important. And we know that when people are facing these terrible diseases or their children are facing these terrible diseases, they have very good reason to push FDA to say, like, get out of the way, move this along.
Holly Fernandez Lynch, JD, MBe:We want to be able to use it. We have other examples where that's happened. And so those five criteria that I mentioned, it's unclear. Is FDA going to hold steadfast and say, we have to see clinical improvement, right? Or are they going to say, well, here are like four of the five criteria were met, and so there's nothing else that's available, and so we'll allow it to go, right?
Holly Fernandez Lynch, JD, MBe:Those are some of the things that I think we'll just, we don't know how it's gonna pan out. We'll have to pay attention to how it works.
Dan McLean:So theoretically, it could be an end run around randomized controlled trials? Is that the correct?
Holly Fernandez Lynch, JD, MBe:That's the worst case scenario, right? The FDA has they've said, right? Like, this will be good where you can't do an RCT, and these are the things that we're gonna look at. But they didn't pinky promise, they're only gonna use it for that. And we know in these other examples, there's been a lot of pressure to go faster and to accept more uncertainty.
Holly Fernandez Lynch, JD, MBe:So I just have that in the back of my mind as something that I'm worried about what could come up in this circumstance. And then I'll just put on my lawyer hat. I should stop pretending to be a geneticist for a little bit and say the way that FDA went about doing this was all wrong. So the commissioner, Marty Makary, and the head of CBER, the Center for Biologics Evaluation and Research, published in the New England Journal of Medicine a two page article describing the plausible mechanism pathway. This is not a guidance document.
Holly Fernandez Lynch, JD, MBe:It's not a regulation. It's two pages of musings about how this thing could work. And FDA has something called good guidance practices. It's a set of regulations that were actually required by Congress that is intended to prevent FDA from making new pronouncements of policy without going through the proper channels of for guidance, you post a draft. It's open for public feedback, primer comments on these draft Right?
Holly Fernandez Lynch, JD, MBe:And so they didn't do that here. They they talked with KJ's team. They've, I'm sure, talked with with others in the scientific space or presumably others in industry, maybe some families, patient advocacy groups. I don't know because it hasn't been happening in public public. In one paragraph at the end of the New England Journal article, they basically say, This is so important.
Holly Fernandez Lynch, JD, MBe:We can't wait. Fair, right? However, that would mean that the government never has to follow policies on important things, right? It's procedures on important things. When McCary was appointed the commissioner, within just a couple of days, he started talking on his podcast or in news interviews about this plausible mechanism approach.
Holly Fernandez Lynch, JD, MBe:And six months later, they published the New England Journal article. So six months is enough time to create a draft guidance doc. So I found that to be worrisome. The other thing is that guidance documents can come and go. Regulations can come and go too, right?
Holly Fernandez Lynch, JD, MBe:The new administration could come in and change it, but regulations are harder to change because they require notice and comment rulemaking. So to the extent that I'm excited about this pathway and think it could be really fabulous for the N of one and a few, I want it to be solidified in a set of regulations. Not that I think another administration is going to come in and get rid of a really great idea, but regulations tell you these are the eligibility criteria. Here's exactly what you need to follow. And for example, if a company thought that their product ought to be eligible for the plausible mechanism pathway and FDA said no, putting it in a regulation would give them some legal to sink their teeth into and say, you said meet these things, we have met these things, and so we should have access to this pathway.
Holly Fernandez Lynch, JD, MBe:So as a lawyer, I wanted to see a different process. I worry about what we're seeing with this FDA, about a lot of policy making by press release and journal article. I'm just getting to part one. Yeah. It's not how things are supposed to be done.
Dan McLean:It you also write, which I thought was an interesting connection with the Chevron decision. It's an interesting point that now because of the Chevron Supreme Court decision, federal agencies, and please correct me if I mangle this, I am not a lawyer, is that the federal agencies cannot rule make in the same way they previously could, and those regulations actually have to be codified in law by Congress. So is that what you're saying? Is that okay.
Holly Fernandez Lynch, JD, MBe:Okay. It's it's very close. I'm trying to think of how how much law professor do you want here.
Dan McLean:Well, and and also just to to wrap it into what you want
Holly Fernandez Lynch, JD, MBe:to Are have
Dan McLean:you imagining Congress codifying a procedure?
Holly Fernandez Lynch, JD, MBe:That would be the most stable approach here. So what the federal Food, Drug and Cosmetic Act states in order for a product, a new drug or biologic product to be approved is that it needs to be demonstrated safe and it needs to be demonstrated effective. And the way that you demonstrate adequate effectiveness is through well controlled clinical investigations. Now, so that raises some questions here possibly about is there statutory authority for FDA to authorize this new pathway? I think probably, right, that you can What does it mean to be well controlled?
Holly Fernandez Lynch, JD, MBe:Well, FDA already accepts external control groups, right? And so you could And natural history studies and that kind of thing. So you could rely on that here. When I said it requires well controlled clinical investigations, Hopefully that plural is coming across. It's traditionally been more than one, but FDA also has the authority to accept just one pivotal study with confirmatory evidence.
Holly Fernandez Lynch, JD, MBe:There's some guidance, actual guidance, not a journal article about what counts as confirmatory evidence that I think could also be satisfied here. But why am I guessing about whether FDA has the statutory authority to do this? FDA should say, here's what we think our statutory authority is. All right, so that's background. You asked specifically about Chevron, which I know people in the Primark community have heard about.
Holly Fernandez Lynch, JD, MBe:The short version of what we mean when we talk about Chevron or Chevron deference is that forty years ago, the Supreme Court said when there is ambiguity in a statute, the courts will defer to reasonable interpretations by the expert agency that's tasked with administering that statute. So if there's ambiguity in the Food, Drug and Cosmetics Act, rather than the court trying to figure out what that ambiguity means as a matter of statutory interpretation, they're going to say, you know what? We might really mess this up because we don't understand this area. We're going to defer to the reasonable interpretation from the agency. I think that makes a lot of sense.
Holly Fernandez Lynch, JD, MBe:Chevron was overturned recently by the Supreme Court in a case called Loper Bright. And the overturning does not mean that a court is just going to ignore whatever an agency decided or recommended. It just means they are not automatically going to give the agency's interpretation deference. So in this circumstance, right, we have a new plausible mechanism pathway and FDA is going to interpret it in a particular way. I think it's unlikely that FDA is going to get sued over this because companies are going be happy about it, right?
Holly Fernandez Lynch, JD, MBe:They're going to say, oh, here's the new pathway. Like it's unlikely a company is going to say, Do you really have the statutory authority to do that? That's what I'm saying, right? As an academic. But here's where it could come up.
Holly Fernandez Lynch, JD, MBe:If a sponsor thinks they ought to be eligible for plausible mechanism pathway and FDA says no, then maybe here comes the lawsuit and then maybe the court is coming in and you've got a judge saying, I know better than FDA and I'm gonna interpret it my way. That's what the overruling of Chevron means, that any judge can say, I know better than FDA, and substitute their judgment for the expert agencies. But the agencies can still regulate exactly as they did before. They're just on shakier territory about whether their regulations will be upheld.
Dan McLean:And so the ironclad way to do that would be to get it into some act of Congress somehow.
Holly Fernandez Lynch, JD, MBe:Exactly. Exactly. Right. So we think this is we. Those of us who are studying this area, right, and the scientific researchers and people who are expert in rare disease drug development think this is a positive development.
Holly Fernandez Lynch, JD, MBe:All right, then let's solidify it. Let's have Congress say, yes, we agree. FDA has this authority and these are the criteria or we're delegating to FDA to determine what the criteria are. Now, that would require Congress to do something. I think this would be a pretty obvious area of bipartisan support, but there's a lot of other stuff going on.
Catherine Batsford:Indeed. Dan, did you have more questions?
Dan McLean:I do, but I think that's kind of a nice conclusion. But with that in mind, what other applications do you anticipate plausible mechanism could be used for? Or even with the gene editing, it's just fascinating. It's hard to know what types of illnesses that can be applied to. I mean, or that could be an unknown.
Dan McLean:I mean, the world could look different in ten years. So I don't know what the future holds for that type of technology the other applications of a plausible mechanism.
Holly Fernandez Lynch, JD, MBe:We've been talking about personalized medicine for a very long Like this is the epitome of personalized medicine. We don't need N of one levels of personalization for many things, right? There's a lot of genetic disorders, right, that affect many people. And you can go through a regular study process for your gene therapy, right? Like we've seen that for sickle cell disease, for example.
Holly Fernandez Lynch, JD, MBe:But there are a lot of rare and ultra rare genetic disorders. And so, to your question, Dan, it's anything caused by a genetic mutation, right? If you have spotted the genetic mutation, if you know where you need to send that guide RNA, this should work for it. It's amazing. It is.
Holly Fernandez Lynch, JD, MBe:It is truly, truly amazing. The cost of gene sequencing has gone way, way, way down, right? Like this is a conceivable thing that's gonna really affect It's really gonna have a positive effect if we can figure out the regulatory approach and get commercial sponsors interested. It's gonna be a game changer for these diseases of early childhood that are caused by genetic disorders.
Dan McLean:So, is kind of a new frontier, personalized medicine, and then the regulations are trying to catch up with that.
Holly Fernandez Lynch, JD, MBe:Yeah, that's right. And it's, you know, look, it's amazing, right? But there are real risks associated with it. We've talked about some of them already. Not foolproof, right?
Holly Fernandez Lynch, JD, MBe:The way the researchers have talked about it is in a way that the rest of us mere mortals can understand it. It's dramatically more complicated than I'm describing it, but the concept is pretty straightforward.
Catherine Batsford:But weighing the risks, right? Because when you fiddle with a gene, how does that affect everything else in the body?
Holly Fernandez Lynch, JD, MBe:But they're getting better about understanding, you know, what the off target effects might be and how to And
Dan McLean:I and I guess with the focus on a lot of people in the primer community and the IRB world, what should the IRBs be considering with this? I know you mentioned the IRB involvement. This is new technology, this is new information. It's hard to imagine being on an IRB in such a situation.
Holly Fernandez Lynch, JD, MBe:Yeah, right. So the CHOP IRB was partnered with the investigators that were treating baby KJ. Look, IRBs have many IRBs, not all, right, but like many IRBs at these leading academic medical centers where early stage research is being done or first in human research are being done, they're familiar with the overarching questions that they need to be asking, right? What is the mechanism of how this works? How does it work in animals?
Holly Fernandez Lynch, JD, MBe:Right? What are the risks that we ought to be looking out for? It's not that you would expect any particular IRB to be steeped in understanding the particular science here. This would be where you would call on outside experts if necessary, where you'd be working hand in hand with the investigators to help understand what the real risks are and how to communicate that with families who have to make these decisions. This is not the typical, I've written up my protocol in the template and I hit submit on and my then a month later I get my approval letter.
Holly Fernandez Lynch, JD, MBe:Like this is working hand in hand with the IRB from the get go of realizing that you want to put this approach into children. Yeah. That's the model that we always are talking about with PRIMR, right? Is that the IRB is a collaborator. Obviously their responsibility is to protect the rights and welfare of the research participants and make sure that the consent is clear, but not adversaries to the investigator, right, or the investigator team.
Holly Fernandez Lynch, JD, MBe:They need to be part of that team.
Dan McLean:Yeah. All so interesting. Catherine, you want to ask the last one and we can land the plane here?
Catherine Batsford:Honestly, I think we had some great stopping points there. This is fantastic.
Dan McLean:Well, Holly, thank you so much for coming on and talking with us. This is really fascinating technology and the regulations that go alongside with it. It's interesting to to see how it all overlaps. So thanks for being here. We really appreciate it.
Holly Fernandez Lynch, JD, MBe:Yeah. Thank you for having me. It's always amazing when I stop and think about these technologies. So thanks for giving me the chance to talk to you all about it.