Dr. McIntosh is a drug developer working in rare diseases at Pfizer. He has managed teams of statisticians across study phases and in a variety of drug types and disease areas, including neurology, ophthalmology, infectious disease/ global health, hematology, and oncology. He has published peer-reviewed articles on various topics in drug development and biostatistics, including development of cell and gene therapies and qualification of digital endpoints in neurological diseases.
Dr. Sverdlov is a Neuroscience Disease Area Statistical Lead at Novartis. He has been actively involved in methodological research and applications of innovative statistical approaches in drug development. He has co-authored over forty refereed articles, edited two monographs, and co-authored a book ``Mathematical and Statistical Skills in the Biopharmaceutical Industry: A Pragmatic Approach''. His most recent work involves design and analysis of clinical trials evaluating novel digital technologies.
Episode Description
When a gene in the human body goes bad, it can cause illness and disease. Scientists have been working for decades to develop therapies to address faulty genes. In the U.S. gene therapy has been approved as a treatment for illnesses such as cancer, hemophilia, AIDS. However, as researchers explore treatment possibilities. The ethics and costs of such treatments remain a concern. A new book aims to provide an overview of the state of gene therapy development which is the focus of this episode of Stat+Stories with guests Avery McIntosh and Oleksandr Sverdlov.
+Full Transcript
Rosemary Pennington
When a gene in the human body goes bad, it can cause illness and disease. Scientists have been working for decades to develop therapies to address faulty genes. In the US, gene therapy has been approved as a treatment for illnesses such as cancer, hemophilia and AIDS. But as researchers explore treatment possibilities, the ethics and cost of such treatments remain a concern. A new book aims to provide an overview of the state of gene therapy development, and it's the focus of this episode of Stats and Stories, where we explore the statistics behind the stories and the stories behind the statistics. I'm Rosemary Pennington. Stats and Stories is a production of Miami University's Department of Statistics and media, journalism and film, as well as the American Statistical Association. Joining me as always is regular panelist John Bailer, emeritus professor of statistics at Miami University. We have two guests joining us today. Avery McIntosh is a drug developer working in rare diseases at Pfizer. He's published peer reviewed articles on various topics and drug development and biostatistics including development of cell and gene therapies and qualification of digital endpoints and neurological diseases. Alexander Sverdlov is a neuroscience disease area statistical lead at Novartis. He has been actively involved in methodological research and applications of innovative statistical approaches in drug environment. His most recent work involves design and analysis of clinical trials, evaluating novel digital technologies. They're co-editors of a new book, Development of Gene Therapies: Strategic, Scientific, Regulatory, and Access Considerations. Thank you both for being here today.
McIntosh
Thank you so much for having us.
Sverdlov Thank you.
Rosemary Pennington
Why this book now?
Sverdlov
So the idea to write a book on gene therapy, product development came to us actually, as early as 2021, when Avery and myself work together in the same company, and the field of gene therapeutics have been advancing very rapidly. And yet, the development of these novel modalities pose unique challenges and opportunities. Both of us are biostatisticians by training. And so in this book, we actually wanted to highlight a pivotal role of the quantitative scientists, specifically biostatisticians in the development of gene therapies. And so this high quality work involves designing top quality experiments, performing most appropriate data analysis, partnering with various line functions in the process, communicating these ideas, and enabling science driven and evidence based decision making. Actually, we have published together a paper called Clinical Design and Analysis Strategies for the Development of Gene Therapies in the journal, Clinical Pharmacology and Therapeutics in the year of 2021. And then we also wanted to expand it into a full length book on the subject, we actually aimed to develop a book that would provide a useful reference and a navigation tool for scientists, drug developers, healthcare commissioners, educators, and other stakeholders. And we chose a format of the edited volume to have various subject matter experts work together on specific topics and chapters of this book. It turned out to be a great team effort and experience, we expanded our professional networks. And we learned a lot in due course. So overall, I think the entire process from a proposal to a publication took us three years, but it was a really fascinating experience. And I let Avery add more to that.
McIntosh
Thank you, Alex. I think you've covered quite a bit of it. I'll just say, you know, this volume was edited by two biostatisticians, myself and Alex, but it has a lot of chapters that are not biostatistics related on the face of it right. So we have chapters on the scientific formulation and development of these products, the immunology of these products. There's a chapter on market access and things that are not traditionally thought of as biostatistical competencies per se. But one of the lessons for us and believe the conclusion of the book, I think, is that biostatisticians and quantitative scientists, like experts in real world evidence and epidemiologists and pharmaco, nutritions and the like can all really contribute to every area of drug development at any decision. Making stages all the way from preclinical experimentation and assay development and validation through the clinical development and then into post approval post marketing. Really anytime a decision is made that involves data biostatisticians should be involved.
John Bailer
Well, you know, so you're preaching to the choir here. So I'm a biostatistician as well. So that's been my, although, you know, it's a very different world right now, in terms of some of the practice some of the stuff that I did was very preclinical back when I was working in that space, so but I'd like you to kind of take a time machine back with us and talk a little bit about what what is gene therapy? You know, what is it that people are doing? Before we even start thinking about some of these other designs, let's sort out the special challenges? Can you give us just kind of a quick overview of what that even is?
McIntosh
Sure, sure. So gene therapy is a very broad class of drugs that affect, and we even struggle for a definition of this, that affects the expression of genetic information. That's how I think of it. So what that means is all of our cells have DNA nucleic acids that are transcribed into RNA, and then translated into proteins, which power all of the activities of our bodies. So proteins can be enzymes that carry out chemical reactions, or hormones that signal other processes or antibodies or structural components. So gene therapies are drugs that correct or address some sort of genetic disease. So purely a disease of the genes and maybe not an acquired disease, or an environmental disease that might have some genetic components, like maybe heart disease, but something that is generally purely genetic in nature. So some people might be born with a genetic disorder that prevents the appropriate expression of cell proteins and results in some form of pathology. So some examples of inherited genetic diseases. Many people may have heard of Huntington's disease, spinal muscular atrophy, cystic fibrosis and Wilson's disease.
Rosemary Pennington
So what are some of the challenges in using drugs like this?
Sverdlov
An excellent question. And actually, in the book, we have a list of seven hallmarks of clinical development for gene therapies, which make them kind of stand out among other classes of therapies and drugs. So first and foremost, these drugs are really supposed to be disease modifying, they're not just palliative. So they target the root cause of the disease. And they don't just try to alleviate the symptoms. And what it means is that ideally, they should be given as early in the disease course as possible. And in fact, there are instances where these therapies can be administered in utero for some diseases that are diagnosed in utero. Second, gene therapies are usually for rare diseases. And by rare, we mean that, it's actually a very important point to make that there is no universally accepted definition of a rare disease. So for example, in the United States, it's a condition that affects fewer than 200,000 people. So it means that drug development is a little more challenging than for traditional therapy, because less is known about the disease compared to the common disease. And, in fact, rare diseases are not that rare, because individually, each disease is rare, but since there are many of them, so in aggregate, it's comparable to a number of people in the US who have asthma or some other chronic disease. So, third, gene therapies, many of the gene therapies, are administered only once. And that's for a number of reasons, which will not go over that. But that means that we really need to get the dose right to make sure that people who are recipients of the gene therapies get a safe and at the same time effective dose. And that makes gene therapies more like a solid organ transplant rather than a pill that one may take every day. And by the way, this also means that healthy volunteer studies cannot be really run with the gene therapies because they're really transformative medicines and they affect the whole body system. So the drug is only given to patients. Fourth, there's no consensus on what endpoints measure pharmacologic activity, so this area is still a bit black box. And so it really depends on the specifics of the therapy, but in simple terms, it means that a lot of work is required to measure what is really happening in the body when a drug isn't this class given to a patient. Fifth, the safety monitoring is quite complex, because different components of the drug can lead to different potential safety concerns. And so there's a need for safety monitoring. And that is one of the key elements of the development of gene therapy. Six, unlike some other more common treatment modalities with gene therapies, it may be quite ethically challenging to justify the use of placebo in a clinical trial. And this is because the diseases are usually rare and severe. And so patients may not really want to be exposed to an investigational gene therapy product in a trial, knowing that they might be randomized to placebo treatment that will not really help for their disease. And sevens, the long term safety and efficacy is very difficult to predict. So it means that the health authorities such as food and drug administration in the US and European Medicines Agency in Europe, require that patients who are given a gene therapy product be followed for five to 15 years to assess the long term safety and other effects of these drugs. So that's a lot. And I think that makes our life challenging and interesting at the same time.
McIntosh
And thank you, Alex. And if I can just share a little bit of like, personal history for both of us, I think we really, when we came to work in this field, it was very, that you know, all of these hallmarks that just listed did not exist, nobody had really written those down and a place for clinical drug developers. And so, you know, the actual basic science going back for gene therapies goes back decades really back to when people first found that there were diseases that were mediated specifically by genes. But the elements really didn't take shape to make clinical products, investigational products until the early 1990s. And that's when some of the first human studies started being done on gene therapies for genetic disorders. And then after that, it took many years until there were any FDA approved therapies. So the first approved therapies came in 2017, and 2018. And this was around the time that it really started to catch both of our attention, and it started to be a topic in our companies. And we really started thinking, you know, how do we do the drug development process from end to end for these really unusual types of drugs. And Alex mentioned rare diseases, you know, with a rare disease, you may have to develop an endpoint to study and you may have multiple candidate endpoints like imaging or fluid biomarkers or clinical scale of function. And you really need to decide what's going to be the leading endpoint for these clinical development programs. And it's not like, let's say heart disease is, again, for that example, where you have years and decades of regulatory guidance on what should be studied in human clinical trials for these types of endpoints. And you may have endpoints that are developed by health agencies like mace major adverse cardiovascular events, for a rare disease, you really won't have that type of guidance. And so you really rely on drug developers on the basic science and expertise of the medical columns you're working on. And also with interactions with health authorities, like the Food and Drug Administration.
Rosemary Pennington
You're listening to Stats and Stories. And today, we're talking with Avery McIntosh and Alexander Sverdlov about their new book on gene therapy. I think the first full chapter in your book is focusing on ethics. And as you were talking about sort of this ethics of the, you know, you can't provide someone you shouldn't placebo in this situation, right? What are some of the other kinds of ethical implications that developing and using gene therapies sort of pose?
McIntosh
We weren't clear that we were going to write this chapter at first, because we thought, well, maybe we can get away with not having this in the book. But there were so many internal discussions that we had had with our clinical teams on different diseases that we were working on about, you know, when would be the optimal time to give a drug to a patient that might have a foreshortened lifespan. But you know, for example, the FDA generally wants you to have human testing done in adults before you do it in children. And so just basic questions like that are, we're really on our minds. And we wrote this chapter, myself and Alex, along with Mimi Lee, who is at Samsung bioEPIs, and has a graduate degree actually in bioethics and she's a fantastic collaborator. I'd like to lay out some of the history of ethics in pharmaceutical drug development. And I actually listened to your ethics podcast that you had, I'm forgetting the guest now, but I listened to that recently. And of course, they mentioned the Belmont Report and, and the Nuremberg Code, and we covered those issues. And then we went into issues that are specifically unique to the gene therapy diseases that are under study. And then specifically unique to the modality of gene therapies. So those issues that might have ethical implications that are specific to the types of diseases that are usually studied in gene therapy, or as Alex said, they're generally for rare diseases. And so that makes the allocation and finding of patient populations challenging, you might not have a lot of information with which to form a clinical development program. And so maybe one of the ways to mitigate that is the use of really robust and innovative statistical designs to acquire as much information as possible and minimize patient exposure to investigational compounds. Now, we always do that. So in a sense, robust statistical design is always an ethical issue, but because of the real rarity of the patient population, that's something that we pay attention to here. The second disease specific feature is that the diseases, as Alex said, again, are often severe. So this can complicate the benefit risk assessment of these products. So quantify the mitigation there would be the quantitative benefit risk assessments early in the drug development process be undertaken before patients have been dosed. And of course, this is a given, but we remind the readers that equipoise should be respected and continually reevaluated in the context of administering therapies to these patients. The third disease specific feature is that not always but many of the diseases are pediatric in pediatric populations. And these populations are particularly vulnerable. And they usually require evidence of effectiveness and adults first, as I said, and so the mitigation there, or the consideration from an ethical perspective is to really have extra consideration to parental caregiver involvement and the writing and reviewing of the informed consent document. Now, the features that are specific to gene therapies, and I'll just go through these quickly, are that they are generally irreversible. So the ability to revise the dose for a patient is not possible, the gene therapies and can these these isn't like a pill that your liver metabolizes, and washes out. And so sponsors and health authorities really need to continually monitor the long term effects, efficacy and safety of these drugs. The other feature is that the intervention, as Alex said, is really multi systemic, so it affects the entire body. And safety has to be at the forefront of the investigation of these products. They are potentially immunogenic, which means they can trigger immune system memory. And this leads to the general inability to read dose patients with these therapies, right, because the second time that you are just a patient, they might have an overactive immune response or their immune system might attack the vector delivering the gene therapy making it ineffective. There is the theoretical risk. And this has never actually been observed. Here's the real theoretical risk of lateral what's called lateral transmission. So these people who are in contact with a patient who is administered a gene therapy could theoretically transmit some of that gene therapy to the contact person. And so health authorities should follow up they have guidance on that should be followed on what are called shedding studies that look at the excreta of patients in early days gene therapy studies, and we have the possibility for these drugs have germline transmission, which means that they could potentially affect the gonads leading to trans gene transmission to the offspring. And again, this is something that's more of a theoretical risk. But robust preclinical assessments of during lot germline transmission do take place as part of preclinical testing of these therapies, with the idea that heritability of gene therapy effects would not be something that would be observed. And we have a small section at the end of this on what we weren't really sure what to call this, we'll call it over correction, which is the potential use of gene therapy technology to alter populations for political or social ends. And you know, there was a case a few years ago for a doctor in China who genetically engineered two young girls with the idea that they would be immune to HIV infection. And this was not done in a regulated way and that doctor was sanctioned and eventually jailed for that. But it's something that we mentioned here that there really should be guardrails in place at the international level to prevent any type of genetic engineering of populations. And that is in place, it does seem like there's a really robust ban against anything like that.
John Bailer
You know, when you were talking about some of the development of this sort of the studies that were conducted, I think I read in one of the chapters, you were mentioning that some of the drugs have been approved with maybe 50 subject’s data, under 50 subjects. And all of a sudden, I was thinking back on some of the lipid trials where there might be 10s of 1000s, in different arms of the trial, where they're looking at the comparison. So you have these issues you've talked about, you can't have healthy volunteers for these studies. That's something that's different. You've talked about, you know, placebo is maybe not even ethical, which is actually true in other contexts as well. So could you talk a little bit more about how the development of gene therapies differ from this kind of traditional experiments, and maybe kind of, maybe that would be sort of a point counterpoint. You know, in a traditional therapy, you know, we'd have this, but in the gene therapies, you don't, you have to do this. So maybe that's one of the ways to kind of give an overview of it.
Sverdlov
So, that's an excellent question to compare and contrast, the more traditional drug development enterprise versus the gene development enterprise. So actually, there are both similarities and differences. But let me start with a very important point that the body of evidence or the quality of evidence generated from the trials of gene therapy should be similar or, you know, it should not be of lower quality you can, we cannot compromise the quality or just giving the fact that it's rare indication, it's a gene therapy. So the requirements are the same as for more traditional therapies. So the challenge is to come up with the clinical development plans that would enable really high quality evidence generation, keeping in mind all the restrictions that are posed on these treatment modalities. So traditional drug development, as we know, consists of several stages. So we have the discovery part where molecules are discovered. And then we have preclinical development, where it's usually studied in animals before you go into humans. And then the really extensive and long lengthy development part is the clinical development where we study start with first inhuman, or so called phase one trials then gradually move into phase two trials to test the activity of the compound, like phase two, a proof of concept trials, and followed by those range findings that are also referred to as phase two B studies. And then the hallmark of clinical development is the randomized control trials where the goal is to test some clinically relevant research hypothesis in a large population of patients with the disease. And so those studies are really large and randomized, controlled. And even after phase three pivotal trials are done, and we show evidence that the drug is working, it's safe and efficacious. And there is a request for marketing authorization to Food and Drug Administration or European Medicines Agency, there are additional follow up studies that are referred to as phase four studies. So it's really a lengthy and expensive development. Now. If we have a severe disease, and it's a rare disease, and we're in the situation of testing an investigational gene therapy product, then many of these trials are becoming not feasible. So the traditional approach to drug development where you have some small studies followed by larger studies and really large phase three trials is not feasible. So in fact, you may end up with one or two trials that are seamless, in the sense that several stages are basically condensed into one trial. So you might have a phase one two, trial for safety and early efficacy. And this is all in patients, not healthy volunteers, and then followed by a pivotal phase two slash three study, where you continue investigating the safety and efficacy of the drug and also generate the confirmatory evidence for the F efficacy. And so for gene therapies, these study phases might be combined. So there's no universal solution. So it really has to be approached in a cross country context specific manner. But the general point is that we have a lot fewer patients in the settings because these drugs are for rare diseases. And then another important difference is that for some drugs, some traditional drugs, there may be many clinical pharmacology studies to investigate drug drug interactions, or there may be studies in some patients who have for example, kidney impairment or liver impairment. And that may not be applicable for the gene therapies because the gene therapies are highly specific drugs and they generally do not interact synergistically or antagonistically with other drugs. So that makes it very unique and interesting.
Rosemary Pennington
Well, that's all the time we have for this episode of Stats and Stories. The book is out now right from Rutledge, so people if they want to read more about it, can read your books. Avery and Alex, thank you so much for joining us.
John Bailer
Thank you so much.
Rosemary Pennington
Stats and Stories is a partnership between Miami University's departments of statistics and media journalism and Phil and the American Statistical Association. You can follow us on Twitter @StatsandStories, Apple podcast, or other places where you find our podcasts. If you'd like to share your thoughts on the program, send your email to statsandstories@miamioh.edu, or check us out at statsandstories.net, and be sure to listen for future editions of Stats and Stories, where we discuss the statistics behind the stories and the stories behind the statistics.