 Hello, everyone, and welcome to the Harvard Organizational Ethics Consortium. I'm Charlotte Harrison. I'll be moderating this session together with my consortium co-chairs, Kelsey Berry and Jim Saban. You are joining us for the concluding session of the consortium's seventh year here at the Harvard Center for Bioethics. It's good to have you with us, and we invite you to join again next year. The overall aim of this consortium is to build a community of colleagues in which to share developments in health care ethics at the organizational level. We ask our presenters to share an unusual ethical quandary that their organizations are facing, along with approaches they are taking or considering to address that quandary. This year, we've heard from a range of organizations, including a biopharmaceutical company and a global center for health security. Today, we hear from an academic medical center. Before I say more about the substance of today's program, while we have the, can we get the second slide up? Great, thank you. While we have this slide up, let's take a quick look at how you can participate in this session. In particular, please notice the Q&A function at the bottom of your screen. If there's a question you'd like to ask, please feel encouraged to post it in the Q&A at any time during the program. After our panel has spoken, we'll field as many of your questions as time permits. Also at the bottom of your screen is the chat box where you can share comments with everyone at any time. Thank you, Ashley. Today, we welcome speakers from Boston Children's Hospital, which is the primary pediatric affiliate, teaching affiliate of Harvard Medical School. Children's is also home to a research community of 3,000 researchers and scientific staff. Recent developments in personalized therapeutics have posed distinctive ethical as well as scientific challenges. Our speakers will describe some of these issues. They will trace the related recent evolution of both institutional oversight at children's and federal regulation for this work and speak to ongoing challenges. Now it's my pleasure to introduce our lead presenter, Dr. David A. Williams. Dr. Williams is Senior Vice President for Research and Chief Science Officer at Children's, as well as Chief of Hematology and Oncology. He is Leland Fike's Professor of Pediatrics at HMS. David? Thank you very much. I appreciate the introduction. I appreciate being here. This will be, I think, a very informative afternoon for all of us, including myself. I'm going to share the screens and kick off the conversation. And you'll see that I will introduce a foundation on which we'll have additional comments on both regulatory aspects and ethics aspects as we move through the next hour and a half. So, well, we tried this before and it worked fine, but now it's telling me I can't share my screen. Let's just see if I do it one more time. Oh, there we go. Great. Thank you. OK, so I'm going to give you the background that has developed over the last several years at Children's, in which we realized several years ago that the evolving science that allowed people to have really personalized therapies was such that we needed a new oversight structure in addition to the IRB to handle a fast-evolving field. And I think if there's a take-home message that I would want you to have is that it is a fast-evolving field. That is, although we have done some to set up a framework to review these studies, that is going to change as time goes on for sure. So by way of background, what we're going to be talking about is evolution of pathway understanding and technology that really allows development of truly individualized therapies. For the most part, what we're talking about are, to this point, severely debilitating or life-threatening genetic diseases that are rapidly progressive in which there is no current effective alternative therapy. And these, almost by definition, are defined by specific mutations which are targeted in a specific fashion. That is, the therapy is really tailored to the individual patient's disease causing variant in the genome. And another evolution that's occurred is that these reagents that we're talking about can be produced really by service contract research organizations or CROs at clinical standards and at a scale capable of treating a limited number of patients. And what we're talking about most commonly and to date always at children's is in this foundational structure is antisense oligonucleotides or ASOs. What I mean by this is that in the past, it's often been the case that the scale and the quality of production of reagents to go on human beings are such that it would not make sense to do an individual patient therapy just because of the cost incurred. But as technology is advanced, that's no longer the case, as you'll see. The other thing is that patients and families are often intimately involved, in some cases actually as funders for the development of the therapies and often at least as collaborators. And as you'll hear about from Dr. Urian and even our IRB folks, this raises difficult ethical issues, not the least of which is sort of futility decisions that I'm sure David will talk about. So the development of these precision therapies, particularly for rare, serious, and progressive diseases, presents really unique challenges and complexities. And these include they can be expensive to develop. And if they're successful, which of course, we always go into the therapy hoping that's the case, it's often not clear how they would then be sustained and how the availability would be expanded to a wider group of patients. And they may have unique or difficult to ascertain risk and benefits with somewhat unknown risk and significant chance of benefits. But because they're first in human, much of this and as you'll see, often no animal model exists, the risk is often very difficult to ascertain. There's often a desire for a compressed timeline because of the fact that these are rapidly progressive often diseases. And that's felt particularly by patients, of course, and families, but also by their providers. And there may be little or no validation of the target and little time to develop standard preclinical data prior to committing to drug or biological therapy commitment. There may be little opportunity for licensing and future development by external drug device or biotechnology company because of the fact that these are individualized therapies with no appreciable market to drive therapeutic development from a for-profit company. And they may not be clearly defined mechanism for cost recovery of the drug development or patient care cost, that is to say, one can anticipate in most cases insurance companies or third-party payers wouldn't be amendable to paying for these therapies. And by the very nature of the fact that these are first in human and complex progressive diseases, there's always the risk of unintended institutional risks. So these really are end-of-one studies and they also have significant regulatory questions. So this came from an editorial in the New England Journal Medicine by Woodcock and Dr. Marx, who's the head of the FDA. What is efficacy proof of concept evidence is needed to justify exposure of an untested agent in human? What's safety data is minimum? What if there are likely to be more than one individual with the same mutation? When or should a different regulatory process be involved? How should initial dosage and escalation be decided? And how can efficacy be determined if disease course is variable between individuals with the same condition? So even though the mutation may be individualized or personalized, the disease itself has natural history that tells us that there's variability in the progression of the symptoms of the disease. So in this setting, it's critical that a thoughtful, balanced, and robust approach to oversight of these emerging therapies be in place so that patient safety is not compromised. Ethical issues are addressed. Limited resources are fairly and logically allocated and institutional risk is mitigated. And informed decisions could be made with respect to financial commitments. So in 2019, so two years ago now, Boston Children's formed an oversight committee on personalized experimental therapeutics, which I chair. And a goal of the processes developed is to add additional value to the current required processes, that is ancillary reviews and IRB reviews, in a fashion that doesn't introduce significant hurdles for a timeline-efficient introduction of the new therapies were indicated into clinical care. So that was the goal of the whole process that we set up in 2019. So in consideration of this complex area and the need for multiple and varied expert voices, the oversight committee, we felt, should include a key faculty with specific expertise in drug biological and device development, translational research, genomics, disease, scientific and clinical knowledge. And initially, at least, these are likely to be in neurologic conditions and metabolic diseases. But on an ad hoc basis, we wanted to be able to call upon faculty with any conditions for its therapy may appear. Biomedical ethics, nursing with expertise in experimental therapeutics, administrators with regulatory experience that may include outside expertise. We thought, importantly, hospital finance representatives should be available and part of the review process. Legal advice, pharmacy and hospital finance, biostats and clinical research design methods, technology transfer, business development, research computing, of course, the IRB and community advocates. So the scope of this oversight committee was set up to be to review and provide feedback for investigator-initiated studies derived from basic research discoveries at children's, Boston children's and, of course, elsewhere. Studies with small numbers of patients in which accelerated review process are requested. That is not a standard clinical trial going through a standard scientific review and then IRB review. And we made a decision early on that any studies anticipating more than two patients would require a standard clinical research protocol and IRB review. That is, truly, we wanted this to be limited to N1 therapies. The committee should also be involved in plans to alter dosing or discontinued treatment. So a little bit more scientific input into this area compared to a standard scientific review committee or data safety monitoring committee in particular. We said from the outset that studies in which permanent genetic correction are anticipated was not the primary focus of the intervention shouldn't be reviewed. So we have a separate formulated scientific review committee for gene therapy at Boston Children's. That has been in place for a number of years and is working quite well. So we didn't want this committee to include oversight of that. We needed to have institutional priorities around resources, both personnel and finances. We needed conflict of interest and plans for mitigating conflict of interest. And we needed this committee to look at the data safety monitoring committee plans to make sure they were adequate in the review of the committee and the view of the committee and, of course, financial considerations. And the committee would be assembled for ad hoc basis to review proposals. We thought this was the most logical since we had, when we started, no idea how frequently these kinds of therapies would evolve. And that's been the case since we started the committee. We really realized this would require short-term decisions about developing a therapeutic to be used and eliminated for patients. Falls outside the standard phase one trial formats. Anticipated to be an accelerated pathway of drug development, preclinical testing, and regulatory review because of the progressive nature of the diseases, realized from the outset that there may be complicated ethical concerns. And so ethics was involved from the very beginning. And we realized that this may require investment of hospital resources that are not likely to be recoverable via standard grant mechanisms or third-party payers so that hospital finance needed to be involved quickly. So some of the data that's requested in our process from the investigator is how the patient is presenting, the data that support the therapeutic strategy that is the target, and the data that shows that the therapy addresses that target, the clinical protocol, the description of the study team membership, the data and safety DSMC plans, conflict of interest and plans for mitigating this ethical considerations and overall funding plans. And this shows you some of the points to consider that we put together to assist the committee and the investigator in putting the proposal together. So does the data presented show that the molecular target is approachable by the therapy ASO? Does the data presented show that the ASO leads to an express protein? Does the data presented show that there is a functional correction of the model system in which it's being tested in? In this case, almost always this is cell lines. Is there reasonably the phenotype of severe life threatening? What's the literature say on that? Is there reasonably there's no alternative therapies and a reasonable timeframe available? Is there evidence that the phenotype is reversible in any animal model if there is one available? And is there a phenotype that appears to be invaluable in a robust method to allow determination that the treatment has an effect? From a financial standpoint, are there likely to be a cost associated with treatments that are not covered by standard insurance? Are there alternative financial resources? And will the treatment actually require hospital resources or the ordinary? And does the case raise ethical issues? So these are the types of questions that the application by the investigator has to address. And these are the questions that we ask the committee members individually to assess as they're reviewing the application. So this gives you a sense of what we've done since the institution of this. We have two end-of-one studies in treatment for Atexatelium tectasia and for KCNT1 associated epilepsy. We have two in development and pretreatment plays shown here and one study that was not initially reviewed by this committee but subsequently reviewed for dose changes in bat disease that's now closed. So the reporting structure is actually also quite important. So the committee will review and provide recommendations to hospital leadership concerning investment of the effort in the project. The review was set up to be an alternative to our currently required department-based scientific review process to provide recommendations also for the IRB. And the committee acts as a liaison between the key stakeholders and the institution, including the executive committee. Our research executive committee is shown here, B-Track, C-Track, and REC. The chiefs, this is a specialized ski beck, it's a specialized financial investment committee and the Office of Emerging Medical Technologies and the clinical research structure in the institution called the ICCTR. And the finding and recommendations are reported to the EVP of Office of Health Affairs, physician-in-chief and surgeon-in-chief depending upon where the therapy is focused from the standpoint of the disease itself. And then after the process is complete, the IRB chair serves as the final sign-off for the therapies that are submitted to the FDA and expanded access form 3926. And this just shows you visually how this fits into the overall schema of research therapy. So on the right is the standard therapy clinical research, which requires IRB review and approval with or without an IND, including compassionate use therapies. There's a scientific review either at the departmental by a Harvard catalyst or because we're part of the Cancer Center by the FCIBCH Combined Cancer Center IRB and Scientific Review, or as I mentioned, the Cell and Gene Therapy Scientific Review process. And on the left is sort of innovation that's not research and is handled in a completely different way through an innovative therapy review panel. And in the middle is what I'm referring to today and this shows you the reporting structure. And just as our process has evolved, it's become a little bit more complicated in the sense that there is on the right a large number of stakeholders in the institution that need to be in the process of the review before implementation. So the review committee on the left here reports into the EVP for health affairs. And then that's communicated to accomplish the due diligence and risk assessment and recommendations through on the right hand, you can see finance, legal, nursing, philanthropic trust, the Experimental Therapeutics Unit, and regulatory office, the proposed treating physicians and the data safety monitoring committee. These all have to be in sync and agree with the process or the proposal. And then ultimately, the EVP, the physician, chief, surgeon, chief communicates with both the proposed treating physician and family. And ultimately, there's an FDA submission. And as we've mentioned already, ultimately a DSMC and IRB oversight. Now, we've now set up a separate data safety monitoring committee because we realized that was going to be repeatedly needed. And because of the unique nature of these end-of-one studies, we felt having a standing committee would be important and helpful. I won't go into that in any detail, but just to say that that committee is up and running and provides input as the protocol is being developed and subsequently reviews the accomplishments, if you will, of each therapy, including requests for changing dosing and intervals, as well as deciding whether or not the protocol should be continued based on the efficacy results. So just quickly, I'll just mention one example just to show you in real time what this looks like. This is an antisense nucleotide therapy for a child with Atexate and Telexamutasia. I won't go into a lot of details, just to say this is a recessive mutation in a gene called ATM. It's a key D&H damage response gene. And these patients suffer from CNSD generation as well as other complications. And the signs of this occurring usually are very early in childhood. There's no current disease modifying therapies. I won't go into the details, but although people are working on this as a gene therapy target, it's not at this point particularly promising or timely. And this just shows you that the disease includes cerebellar degeneration. I won't go into details here's the reference if you'd like to see it. And the disease continues throughout adulthood with continual atrophy and CNSD deterioration. Now, the mutation for this occurs in a way that allows it to be amendable by antisense nucleotide therapy. And you can see the gene here with the mutation causing an abnormal splice. And that's amendable then to oligonucleotide treatment to restore appropriate splicing of the gene and expression of a normal protein. And so this is a single gene disorder that's fatal, debilitating, there's no effective therapy. It's amendable to oligonucleotides. The CNS disease is caused by haploid insufficiency. And so the expected correction of the genetic defect would improve the disease trajectory. There's sufficient natural history data to understand the risk-moving effects. There's sufficient outcome measures that could robustly monitor the patient for progress or lack of progression of the disease. This family that was involved was capable of understanding and tolerating, consenting the risk in certain these complexities. And we have, Tim had set up Tim U, clinical monitoring by an independent disease expert with multidisciplinary evaluations. And so the ASO he developed is shown schematically here. And the committee reviewed all this and just to give you a sense for the committee's report, they felt the phenotype was indeed disease, is severe by threatening. There's no alternative treatment available. The presented data showed the molecular target is approachable, there's no good animal models, but the disease patient-derived fibroblast demonstrated effective reversal of molecular defects, the misplacing. And the data actually showed some functional correction of the fibroblast based on partial restoration of a downstream target of the ATM protein. The disease also said while the disease phenotype is severe, it's not clear if a positive therapeutic effect will be measurable in a robust fashion. And with respect to the scores, the investigators stated to be used the video exam would be scored by two independent raters on a blinded fashion. The committee had questions about how those raters could be blinded in an N1 study. The quantitative MR imaging that was proposed was maybe sensitive and quantitative, but it's not clear that the methodology would yield valuable data in this setting. And the committee suggests it may be good to bring in neuro radiology expertise and include the fusion MRI as well. And there were no ethical concerns raised. So this gives you a sense of the feedback that the committee provided to Dr. Yu, who then addressed these issues with a amended protocol. And ultimately, this trial was recommended for approval to the hospital and was initiated. Now I'd like to just close by one other thing. As I mentioned, this is a fast-moving field. And recently the FDA reduced, released new guidance for this type of therapy for comments. And under these new regulations, I won't read this through. I think this will be addressed probably by Susan Kronetsky. The FDA will actually now require IRB review in a way that's analogous or similar to any other clinical trial. So this is a change that's being proposed going forward. And I think a recognition of the FDA that these therapies are gonna become much more prominent and prevalent in the future. So finally, I just felt it was important to recognize how many people have contributed to all this. Again, I won't go through the names here, but you can see by the representations here, what we've tried to do is set up a broadly based oversight committee that includes all those kinds of expertise that I mentioned at the very beginning. Okay, so let me stop there. Hope I didn't take up too much time. And I'll stop sharing at this point and turn it back over to you, Charlotte. Thank you, David. Thank you for that comprehensive overview. Next, we're gonna hear from three other members of the Children's Hospital Oversight Committee or ACPAT that David has just described. Dr. Tina Poussaint is the Chair of the Institutional Review Board at Boston Children's. She's a neuro radiologist who holds the Lionel W. Young Chair in Radiology and is Professor of Radiology at HMS. Susan Kornetsky is Senior Director of Clinical Research Compliance at Boston Children's. Dr. David Urian is Co-Chair of the Hospital's Ethics Advisory Committee, Associate Director of Child Neurology and Neurodevelopment Disabilities at Children's in the Residency Program. And he holds the Charles F. Barlow Chair in Neurobiology and is Associate Professor of Neurology at HMS. I believe Susan and Tina will begin and then David will speak. There you go. Can you see that? Is that okay? Yes, okay, great. So this presentation will be devoted to some of the IRB and regulatory issues. I will present a little bit and then Tina will follow. So a couple of things when we think about how the IRB fits in, I think the first question are our end of one trials for personalized therapeutics really research. And as far as an IRB, the way we think about things, there are two ways that we think about one. One is a regulatory definition, a systematic investigation for generalizable knowledge. And so there are lots of questions when we think of end of one trials of the idea, how generalizable is this when it is a personalized therapy. Under FDA, FDA defines this as a clinical investigation and FDA recognizes that the IRB structure and review. Susan, can I just interrupt? I'm sorry, but could you put on your slides on slideshow because we're not seeing them advance. You're not seeing advance. Okay, you should slide. So let me see. Okay, is that better? Yes. Yes, thank you. Thank you, thank you. So the Food and Drug Administration refers to the use of a test article. And since the use of these therapies does require an IND, it really doesn't matter to the FDA, whether it's one or multiple individuals. So this does fall under FDA and does fall under the oversight of IRBs. Now, as far as the way that the FDA is considering and reviewing these INDs, they are using the regulatory pathway of what's considered an individual expanded access. And so this requires on an individual basis that the investigator applies for an IND and it includes a treatment plan. It also includes a specific type of form. And initially, and David referred to this, the investigator can use an option that bypasses full committee review. And on this form, there was, there's a choice that you could obtain authorization by the IRB chair and not have it go to the IRB. So that was initially the way that, in a regulatory sense, this went to FDA. However, as David mentioned, in January this year, there were specific recommendations that came out in draft guidance that now requires that this go to the IRB, a convened IRB to review. So what I wanna do is just talk a little bit now about some of the complexities of having an of one trials like this go to the IRB. So I'm not gonna go over these, but these are the standard regulatory requirements that an IRB needs to consider before they can approve any type of protocol. And in this situation, we have to think of how to apply these criteria for one individual patient. Most IRBs, when we review things, it's for a group of patients or certainly a small group of patients, but really we haven't thought about how to think about these things on an individual patient basis. So the question is, is there a mismatch? And I'll just point out some of the issues that we would consider. Do IRBs have the expertise to consider science as it relates to the review criteria? And I think at children's hospital, this is one of the important parts that there is an oversight mechanism in review before it comes to the IRB. But if there wasn't that type of review that existed a very in-depth scientific review, I think there would really be questions about the expertise on the IRBs and what they would need. IRBs generally look at risks and benefits for protocol versus an individual subject. It's a different way that we need to weigh the risks and the benefits. And then one of the other challenging things is equitable selection. And how do we think about equitable selection when personalized therapy is developed for one patient and funding often comes from a family or family foundation? So how does an IRB think about, is this an equitable selection? How do we apply this criteria? And then also I think it's really challenging to think about the process and the informed consent and what is a meaningful informed consent process? I mean, all the work for an individualized patient and therapy has already been completed, often funded by the family. And now it comes to the IRB with an informed consent. And so how do we think about this in a meaningful way? Very different than when you think about it for a clinical trial for a group of individuals. The other issues about data safety monitoring, what criteria can be used here at Children's, there is a process now that we do have a data safety monitoring group, but IRBs need to think about how to do that and how that should be written into the protocol. There could be issues of privacy and confidentiality as it relates to media attention. And also one of the things is there's certainly challenges in reviewing and timing of modifications in therapy and monitoring along the way. So often when you're doing personalized types of therapies, the approach may change or some ideas. And so having those types of things for individual patients come in as amendments to the IRB also represents challenging. And then lastly, and this is where someone, David will certainly get into this. It's really hard for an IRB not to be aware and concerned about some of the organizational ethical issues and concerns, but obviously the IRB needs to keep within their jurisdiction. But in some of those things, it would have implications for satisfying criteria for approval. So there's a tension there about the IRB role. And I'm going to stop there and I'll advance the slides. Tina, who is our IRB chair, will continue. Thank you, Susan. Well, it's really wonderful to speak to you today on this topic. And I would just like to reiterate what David had said in terms of the importance of OCPET and the reliance on comprehensive expertise for evaluation of these protocols. Many times the IRB does not have the total comprehensive scientific expertise to evaluate these. And so it's very important to have a focused expertise involved. With regard to the data safety monitoring board, it's also very important to have adequate representation on the board. And it really depends on what type of protocol that's going to be done. And this is the only study where there's a central data safety monitoring board that's specific just to this particular type of therapy. And it's important to have, of course, on that board added expertise and all other domains. Next slide. So there's really an issue of knowledge obtained from the protocol. Is it generalizable when you have these N of 1 trials and can it be translated? And how do we equitably select subjects for participation? There's the issue of funding and where this funding source comes from, how available funds are. And of course there are issues of access and equity. If someone can pay for this type of therapy versus those who cannot. Next. Of course, Susan mentioned the consideration of the individual versus the group. We have to really consider the changes and modifications as she mentioned for the individual and these protocols must be reviewed by the IRB prior to the changes and modifications occurring. And then there's a question of evaluation of success in the protocol. How do we measure in these N of 1 trials? Improvement, how do we assess stability or how do we determine success? And so it's very important to have inclusion of objective assessments and endpoints to evaluate the therapy is necessary. And of course within all of this, we must minimize risk. So thank you very much. Next, I'd like to introduce Dr. David Durian, Durian who will be speaking next. All right, so I just unmuted and I'm trying to share my screen, but it says only host. Can you see that? Yes? Great. So I'd like to, in the time available to us talk about some of the ethical considerations in individualized or precision medicine trials and especially genetic disorders and particularly with attention to N of 1 trials. And I think that I don't have any financial disclosures. As you know, I'm on the octet. I am one of the gang of 12 that was involved in ethical challenges confronted with providing nursing nursing and another subsequent article about the role of assessment of neuromuscular disorders in terms of crisis standards of care. So at least you deserve to know that before moving ahead. And one of the things I'd like to spend our time talking about is thinking that we have both, what I'd think of is micro ethical issues. That is the ethical issues within the protocol itself as pertains to the one or two children and the attendant structures around them versus the macro ethical issues which some people have already been raising in the Q&A. How do we determine who gets to get in the queue in the first place and how do we make that? And I would take our attention to Lawrence McCullough, a medical ethicist who has made the argument within the pediatric ethics space that parents and physicians serve as co-fiduciaries of a child's best interest and each has a zone of maximal expertise and therefore influences we're trying to walk through these issues. Parents, for example, know their dreams and hopes for a child better than anyone else and therefore are expert in that. And physicians actually usually know the medical outcomes and possible risks better than anyone. And so there are instances McCullough will argue that the physician community may ethically curtail usual parental autonomy in the face of medical risk that's too high really regardless of parents wishes. Traditionally, this has worked well as a construct in our established model that I think we're all familiar with the phase one, two and three trials. We know where and when we feel children and or dependent offspring can fit in and when they can't. And of one trials, however, by their very nature collapse phases one, two and three all on top of one another. And while there may be either compelling or highly suggested animal work this may not be completely equivalent to the human experience. A very good example of that is spinal muscular atrophy where the animal models were significantly limited because the disease that rodents get is just really not like the human disease even if it bears some biologic similarities and has conserved genes. Animal work in some instances may be limited to toxicological studies because there is no good animal model which should at best therefore afford us lukewarm comfort as we think at the individual level. A good example of this would be Batten's disease where there was a protocol that you already heard from Dr. Williams which has been closed. There really are no good animal models for Batten's disease. A patient may present with a unique molecular mechanism which may show promise for a technology such as ASOs. But in the end we face the ethical issue of administering an agent we think that will work. We believe it's not that toxic for disease process of which we may have very limited biomarkers predictive of efficacy to a minor child for whom we are the primary co-fiduciary of best interest in a medical sense. This is balanced against the progressive usually fatal nature of many of the diseases that we're talking about here. So we have everybody operating from their own moral sphere parents who are really desperate because their child has an intractable and progressive medical disorder. We want you to do everything for our child. Physicians who have a great degree of uncertainty you have no idea what everything actually is is a common refrain. We have well intended investigators we can't sit by and watch this happen if we know something that we think might be able to influence this. And we have at the center all of this a child whose wishes fundamentally were never known or are unknowable given the nature of their disease and their age. So one of my favorite ethicists of the 20th century Graham Greene reminded us in the quiet American God save us always from the innocent and the good. So how is it that we pick our way through this kind of a problem? I think one of the issues that confronts us almost immediately is one of justice. And how is it that we determine access? Does everyone have equal access on a fair basis to a new technology? There's also the notion of fair innings. Does everyone have an ability to benefit from a treatment that might either give them a longer life or a better life? What are the assessments that we use in the community of persons with significant neurodevelopmental disorders? Disability-adjusted life years and quality-adjusted life years have a very sketchy reputation because they seem to denigrate the dignity and value of lives lived with certain disorders. And then finally we have the very thorny issue of prioritization. How is it that we decide which trials will go first by the need, by the severity? I think as Americans we would do almost anything we can to avoid using the R word rationing. And then finally, funding. How and who decides what work gets funded and how do we walk our way through this? So if we think about models of funding extant in research in the United States, we can think that there are several different approaches. There's disinterested philanthropy, for example, from disease-specific organizations. There's the common will that is public interest as represented in the United States primarily by the National Institutes of Health. Afflicted families with means to support research. And then the marketplace itself, a biopharmat plays an increasingly important role in the development of new therapies. So I think what we can do as we walk through this, if we go to Frances Cam's approach to the trolley problem, she's argued for a bottom-up deontology that is your choices that you make demonstrate your beliefs and principles rather than your beliefs and principles determining your choices. And I think I can make an argument that our choices that we make as a society about funding novel research such as N of One Trials will probably tell us lots more about what we actually believe as a society, than mountains of scholarly papers or piles of regulations or helix of white papers. So if we're thinking that we need to find a model for an approach to multiple different kinds of funding and therefore ultimately what we might think of as charity or philanthropy, Moses Mamonides worked through this problem during the convivience in Umiad, Spain. He lived in a multicultural society, so not all that different than the one we live in, and one that was undergoing rather remarkable technological transformation in its time. And he came up with a way of thinking about how it is we accept charity or philanthropy in various scenarios since it was an important ethical problem of the time. And he came up with a hierarchical model and I won't read through all of the slides, the text here, but he felt that the highest level was to endow the afflicted with such things as to render them never in need of being a recipient of giving again. The next level is where neither donor nor recipient know who they are and the giving is a show of beneficence alone going down the level. Till we get to the next level of giving is a known recipient after being asked to give gladly but inadequately and the worst circle he felt was the lowest level was to give unwillingly. So how is it that our funding mechanisms line up in this model that Mamonides proposed to us hundreds of years ago? So I would argue that federal funding is by and large at the second level of giving virtue. There's large numbers of people who give through their taxes and others receive researchers and the patients in their clinical trials and both are fundamentally unaware of one another's identity. So from each according to their abilities and to each according to their needs. And we have an authority that should be impartial and ultimately ignorant of the donor identities and mask from the essential identities of the ultimate recipients making the decision. In disinterested philanthropy, for example, a very large disease specific foundation with the scientific advisory board, the donor does not know the identity of those who benefit from the gift by and large. So you can think of any large named laboratory research initiative, but those benefiting can see the name on the building. So we have examples of that if one walks into a children's hospital to the main entrance you can see to the right an example of such disinterested philanthropy. And then finally we have a model that is fundamentally being used in the context of most and of one work these days be afflicted with means. That is a family foundation which is established for their specific child's afflicted illness. The donor and the recipient know one another and arguably there's an ask involved. So this is Mamanides sixth level of giving if you're hierarchically inclined. Mamanides was particularly wary of this in the commentaries that he made on charity because he felt that the nature of being subsequently beholden of donor to recipient and recipient to donor was an ethically treacherous place for human beings to be. In the end we can ask as people have is the donor actually renting the lab or the unit of the institution for a period of time. And since this is an old and since time is the ultimate zero sum game in medicine what is not happening that might otherwise happen if we engage in such a process. So that is, does the donation set the agenda? We accept this on the part of the NIH. The NIH comes up with principles or plans or requests for proposals over the course of the year on the basis of a national strategy. We accept the disinterest in philanthropic gift because it may align with our strategies and institution and a larger body has come to the determination that this might be the most prudent way for this part of science to progress. But how do we protect against this particular kind of donation that is for a single end of one study either hijacking our strategy or taking its place in line on principles that may not necessarily align with our institutional principles of justice and fair access. And then we can finally think of the marketplace which ultimately relies on the potential for the commodification of the discovery. And this isn't inherently bad. There's lots of our essential existence that's commodified food, housing, travel, education. These are regulated in our ethical conduct in a different manner, however, than he is giving and it can be fraught, I think, to try to deal with the given ethical issue in a system not designed or intrinsically able to assess it. So we tend to consider religious and other exemptions for vaccination under the aegis of autonomy, but too great a deference to autonomy and insufficient consideration of justice as in the innocent contracting measles because of your autonomous decision not to vaccinate your child has led to episodes of calamity here in the United States. Nusa-Nurson is very expensive for a variety of complex reasons we don't have time to discuss here. And this is the oligonucleotide that's used to treat spinal muscular atrophy when I came into neurology and a relentlessly fatal disorder in its earliest forms. In the United Kingdom, the calculus for national health service coverage for any given medication includes a cost threshold for each quality adjusted life year gained above which the system cannot and will not go because its resources are finite. The UK therefore came to the decision that it would not support the use of Nusa-Nurson in its patients with spinal muscular atrophy. Our ethical metrics, however, of fair innings and autonomous patient choice led to a general acceptance of the agent by the FDA including categories of the disease for which data were not yet available and accepted its cost. Both of these were ethical metrics but they're very different ethical metrics and the two countries came to very different conclusions about what to do in this setting. I would submit that our ethical assessment for public funding, disinterested philanthropy and targeted philanthropy can use a common framework but we likely need a different framework for marketplace based funding. And so our current assessment structures as we've already heard, traditional IRBs may not have all of the expertise and mental models needed to consider these emergent technologies and we may need to think new models of governance and oversight for these trials. OCPET represents one early attempt to do that but our experience will tell us how it is it needs to be modified based upon the data derived from the decisions we make. And so I'll just finish with a quote from my favorite abolitionist Tim by James Russell Loll time makes ancient good uncouth. Doubling back to what David said to us at the beginning that this is a field that is rapidly evolving. Thank you David and thank you Tina and Susan. We have a number of issues on the table and we're luckily now ready to hear from our outside discussant, Dr. Martin McNeely. Dr. McNeely is a visiting lecturer in the Department of Surgery at the Beth Israel Deaconess Medical Center in Boston. He co-chairs the Surgical Ethics Working Group at the Center for Bioethics at HMS. He is also a professor emeritus of surgery at the University of Toronto, Martin. Martin you're still muted. You're still muted Martin. You're muted. There we go. I hear you and you hear me. I wanna compliment the organizers for a very cooth approach to this problem. I love that word. About 20 years ago, the surgeons in chief at Toronto General Hospital and the hospital for sick children asked me to help organize the issue of every day we get requests from surgeons who wanna try something new. They wanna invent a new operation where they attended the meeting where they learned about a new device or technique. And I called my peers all over both countries to find out how best to manage this problem. And the general answer was, we just try stuff and if it works, we keep doing it. And if we don't, if it doesn't, we don't. I had excellent advice from Susan Kornetsky and Bob Truth when I visited the children's hospital at that time. And I learned there and subsequently that the IRB is not ideally suited in ways that Susan brought up in her presentation. The best written work on this subject I thought came from Patrick Taylor who is a counselor to the children's hospital. And his article, I'll give the reference to Charlotte for any who wanted. But his title was Oversight of Innovative Therapy without mistaking it for research. It's a very concise and well-worded title. He's refuting the notion that this should be entrusted to the IRB despite the recent suggestion that NF1 studies should be run through the IRB. I have a Maimonides question for David Urian. And it's about the dislocation of the missions of a given institution by a new powerful force, which could be money, it could be a pandemic, it could be a sensational discovery somewhere. And there have been examples of that that were quite dislocating. When coronary surgery was developed at the Cleveland Clinic, the educational mission was dislocated by a tsunami of coronary bypass operations, completely disrupting the training program. And residents had to be sent to other institutions to gain their experience with congenital heart disease and general thoracic surgery. When transplantation under Tom Starzell was overexpanded at the University of Pittsburgh, it became a transplantation mill as the Cleveland Clinic had become a coronary mill. So, and currently we're experiencing dislocations due to COVID-19. So for example, last night I was instructed how the Toronto Hospital System was redistributing surgeons, residents, and so on, to meet the current expansion, the current surge. At Columbia, one of our surgical ethics fellows told us, the operating rooms were converted to ICU rooms in an ICU suite, which displaced much of the surgery at Columbia. Each operating room became a two-bed ICU room with the equipment and personnel that were relatively well prepared for that. Last night I heard a seminar of how we, not necessarily in my demographic group, but how most of us could be retrained on a short course to become the ICU physicians and nurses who are needed during the current surge. So my question, which I think I'll address to David Urian, is how do we protect the institution from this kind of disequilibration if the wealthy donor insists on a maximal investment. The work that David Williams described was expensive. It was carried out by personnel of the children's hospital. It used equipment and space that was necessary for its completion. And so I wonder where is the institutional oversight to protect the institution from this kind of distortion. I see traces of institutional strength in the committee that I think would probably be adequate, but I wonder if it might not be a problem to be referred to the ethics advisory committee rather than to a more narrowly focused group. We, so far in the 20 years of experience at the Hospital for Sick Children and Toronto General, haven't encountered that kind of problem, but it does seem that institutions have to be ready for protection of its multifocal mission to protect the institution from this kind of distortion. I think it's an admirable effort on the part of this committee to come up with a solution for the N of one patient with an orphan disease. And I'll close by saying N of one is not a necessarily prohibitive attribute of these studies. Many of the great advances in medicine have started with N of one cases. Heart surgery began with Dr. Robert Gross at the Children's Hospital with an N of one operation on the patent ductus arteriosus. And transplantation began with an N of one transplant between identical twins. And only later with the development of refinements and adjuvants such as immunosuppression and HLA tissue typing could transplantation be expanded. Similarly, cardiac surgery was expanded by the development of the heart-lung machine. So N of one is not necessarily a troublesome aspect of this kind of research and eventually N of one studies such as Dr. Williams is doing become generalized using similar or the same tools. I would like to ask Dr. Urian what his opinion is about the conflict of commitment when institutions are asked to devote too much of their capital to a particular donor very first particular patient. Thank you. Well, thanks for the question, I think. So I guess the way I would think about this is back to that model for lack of a better term of the microethics and the macroethics. I think that as an entity like OCPAT can be very well poised to look scientifically, ethically and at all the other implications of any given single trial before it. And that's probably all that it could logically be asked to do since that's all that it's really charged to do. I do think, however, that we have the macro issues that we spoke about. And those are at the level of institutional strategy and even beyond societal wishes and strategy. And that requires a deeper and broader conversation with even more stakeholders because I think as you alluded to we have to balance all of the various interests of the institution. If we are dealing with a problem like N of one trials we probably have sufficient time to do that. If we deal with something like the onslaught of a pandemic that may not give us time to think about that in terms of how that can alter or sometimes even subvert institutional priorities. But I think in this instance we at least do have sufficient time to have a larger conversation at least at the institutional level with people who are charged with the vision of the ultimate goal and direction and strategy of the institution. And then also of a wide group of stakeholders from the community at large. Lots of people look to the institution where I've worked for decades now with expectation. They certainly deserve to be at the table in the same way that families with desperately ill children deserve to be at the table. And I think it's out of that process that we could probably decide what it is we will do at a level of institutional prioritization. And to get back to circle back given the culture in which he lived Memonides was a large believer in people sitting down and talking, talking and talking until they came to some solution to their particular quandary. And so I think that he would probably remind us that human reason is a great gift and should be used and hardest for such a problem. Thank you. This is Dave Williams. Maybe I could just add to the conversation here. We were careful when this was set up in contrast to the way our scientific review process normally occurs at children's. We were careful that the recommendation and that's what it is around the end of one studies go to the physician in chief, the surgeon in chief and the chief, sorry, the executive vice president for health affairs as the leading physician healthcare representatives of the entire institution. And in addition, as you saw as the process evolved and we learned, we now require input from a wide variety of stakeholders that are not on the committee. That is, as you've said already, ethics again, the business office, the philanthropy office so that there is a wider view of the institution's commitment and fairness that's brought into this. That's in some ways quite distinct than the way we normally do a scientific review and IRB reviews. It would be extraordinary, for instance, Susan may wanna comment on this or Tina, it would be extraordinary for in a normal customary work day environment for clinical research occurring at children's for the physician in chief or the EVP for health affairs to have a yes or no say in allowing something to move forward. Now, it's not to say that they couldn't do that under some extraordinary condition but it's not the customary way things happens. So we were quite, I think, thinking about your comment as we set this up. It's an extraordinary review and implementation process reflecting the extraordinary and complicated and of one circumstances. Thank you, David and David and Martin for posing that question. Martin, did you have any further questions or comments or are we beginning our Q and A? I think we've kicked off the Q and A. Fantastic. And thank you, Martin, for laying the foundation with your various remarks on innovative treatment and the sort of larger picture of the context in which these questions are arising. I think you've also highlighted, David and I packed the whole panel the particular role of the academic medical center which is in the center of a number of these questions with funding from other parts of government and civil society and in fact, making sense of and just triangulating the various influences and really raising the questions that arise when this kind of new practice is before us and has the potential that it has. So Kelsey Berry is going to be curating our Q and A and I wanna take this moment to encourage people in the audience to put your questions in the Q and A so that speakers can address them and we look forward to hearing from you. Kelsey, what are you seeing so far? A lot of good questions. So just to begin, it's a question for I guess all of the panelists here. Would you agree that by definition, N of one trials seek to benefit the individual patient as their primary goal so that there's really no possibility that the patient's interests would be slighted in the course of attempting to obtain generalizable knowledge? I'll wait in where Angel's fear to tread. Actually, I'm not sure I do entirely agree with that because one of the issues we have is that frequently the disorders, as David pointed out, have limited biomarkers in terms of monitoring progression and therefore one of the big issues that comes up for the data safety monitoring group is when and if dosage escalation of a given therapy occurs and under what means and when do we say we've reached the point where further dosage escalation is no longer useful. So that's a way in which I'm not entirely certain the fact that it's an N of one trial protects the entirety of the patient's potential interests. And I think it's a particularly thorny one when for most of the disorders that have come at least to OCPAT so far have limited reliable biomarkers to measure as proxy and therefore making decisions about dosage escalation from. Thank you, David. Do any of the other one of the panelists want to weigh in on kind of this question about the generalizable knowledge component of some of these N of one studies and how that's considered in the context of OCPAT or the IRB, the new kind of role that the IRB will be playing with respect to these studies. Well, I agree with what David Urian said, which is that on the one hand, just because it's an N of one study it doesn't mean that there's no generalizable knowledge that is generated. So it turns out of course that in the while there may be a private mutation that's addressable by an ASO in a particular disease phenotype as we've seen once the technology and the chemistry of the ASO is worked out, then there's possibly other mutations in that same gene that could be addressable using the technology even though they are not the same mutation as that particular patient has. And so in the sense that there's an experience that's generated about the safety of the oligonucleotide which largely will not be or likely to be sequence specific and the progression of the disease, which as we've already talked about while variable from patient to patient one patient being treated may allow some recognition of how that progression is going to occur in the next patient. Those are things that could be recognizable or and applicable to other patients. And I'll just address another question since I'm at it that I saw which is does OCPET require the investigator to a priori make some condition or promise around publication? Of course, I shouldn't say of course but no, at this point we don't but the reality is it's likely, very likely that these experiences will be published but there's no requirement by OCPET. And in that sense it is an individualized therapy that is what OCPET is trying to do is make the best decision based on science data for whether or not there's a likelihood that the therapy could be helpful and non-toxic. It's not making a decision that this is going to be extrapolatable to other individuals and therefore the requirement there's no requirement for the wider publication of the data. This is not as I'm sorry as Susan pointed out this is in the traditional sense not researched therefore. Thank you, David. Just to press on that point a little bit as we continue thinking about generalizable knowledge I am curious about the kind of aftermath of some of these studies and whether there has been you've kind of mentioned there's an expectation of a greater frequency of N of one trials occurring and just curious about whether you see a potential for Boston Children's to be involved both in sharing the knowledge that comes from some of these N of one studies and expectation that perhaps others might benefit and also balancing that with the incredible expenditure of hospital resources that you've mentioned go in to doing any one of these N of one studies. So I wondered if you could weigh in on that balance. Well, these are I guess I will go first but I hope some of the other panelists may want to weigh in. I think these are very difficult issues to address in the sense of how does one weigh institutional expenditures if you will either time or money versus the number of people who may seek these kinds of treatments. I'm not sure in this case, I'm not sure any of us have a crystal ball to be able to answer that question. We certainly understand that there may be more frequently people desiring this kind of treatment because as you know, we are understanding more and more the genomics that are associated with particular phenotypes and our expectation is that as that occurs, there'll be a likelihood that more opportunities will arise for the application of ASOs. And so I think in that sense, I'm not sure we have an answer at this point as to how in the future we're going to make sure that the therapy is equally available to anyone who wants it. But I would argue that that's not necessarily so different than many of the therapies that we currently administer that are high priced therapies, if you will. And the other thing I would say is we have been, I think aggressive, both talk to you and some of the rest of us in trying to use our experiences to help, for instance, the FDA understand how they can best play a facilitator role in overseeing these kinds of therapies. So we've had a number of conversations with the FDA. We've been present and asked to be present a number of their own deliberations about these things. And so in that sense, we certainly are trying to use our experiences to the good of other people and other institutions. I don't know if other people want to weigh in on this. This is a particularly insightful question that's difficult to answer, I think. I think that one of the things we're talking about is fundamentally we're talking here about rare diseases. And those have historically been hugely underfunded, under researched, under resourced in terms of moving toward cures just because they are, I suppose, at some level rare diseases. And while some of them have predilections in certain populations, many of them are equal opportunity employers and afflict children across any of a number of demographic categories. You know, as somebody who's been practicing neurology for closing in on 40 years, I know many of these disorders horribly well along with the families. So I understand the impetus that families feel that now that there's finally something on the horizon that might help them. But that has to be balanced against who does, in fact, get access to this. And both the issues that are raised not only a fiscal capital, but also a social capital in terms of mobilizing the resources of an institution like this. And those are hard questions that we will need, I think, broad and inclusive discussions to determine, you know, who is a society we wanna be moving ahead, who is an institution we wanna be moving ahead to make certain that this does not accelerate healthcare inequities. As opposed to move against them. So I would just like to say that, I mean, this doesn't solve the issue, but you know, one of the thoughts that, you know, we've had or have I've had is it's not always possible that when you have, you know, families wanting to fund something for, you know, their own child or foundation, to open into a discussion about, you know, the potential for other subjects or a second subject. And we don't think we can, that's not gonna solve the problem that we're talking about in inequities, but it does raise an issue whether there are other ways that there's, you know, there's one particular, but at least we know if there are others and is there a potential to be able to also as a commitment to doing this after this, you know, to another child or other children. It's all about raising money and that may or may not be feasible, but that's something that, you know, I've thought about is a very, very small baby step. Just to add a dimension to that question, if I may, there have been suggestions in the relatively limited literature on the derivation of benefit from N of one trials, you know, that one way of addressing issues of access would be through a consortium or a public-private partnership involving government and industry as well as medical centers. And a question arising from that, I mean, that's coming from some of the lead FDA regulators and others, what would be the role then of the academic medical center and do people on the panel think that it would be feasible over a period of time to work in a setting like that? Well, I think we, so my own area is not in a one studies, but my own area is includes gene therapy and those gene therapies as they're applied as you know, for the last 20 some years are often in rare diseases. As Dave Uron mentioned, David Uron mentioned, children's in particular, many quaternary care pediatric institutions have a lot of focus on rare diseases because rare diseases are over represented in the pediatric age group. And in those circumstances over the years, I think very effectively we've developed informally public-private partnership where even for rare diseases, we've been able to work often with biotechnology companies or biopharma to address the development of genetic therapies for rare diseases. So I would as just speaking for myself be completely comfortable with that type of arrangement. And I think it would be likely that a small number of pediatric institutions, they have a research base would likely be places where those kinds of partnerships would develop because that's where often the disease specific expertise exists for these rare conditions. As again, as David Uron implied in his own case, also it's where the patients are, where diseases patients often evolve into coming to a smaller number of institutions and that have a research base. So I think that would be one way to approach this that would at least from my standpoint be a very positive way to approach it. So I think we might have time for just one more question. We'll ask one from Bob Trug. So how do the ethics of off-label use of medications which can be an N of one differ from the use of experimental treatments like ASO? And if they're the same, does that tell us we should be insisting on greater oversight of these off-label uses of medications? I mean, I can, as a non-medical person here, I off-label use of medications, there is data, it's been used before. It's been approved, it's not a first in human trial. And so I do see that differently as ASOs, at least right now, as we do more of this and have more information, but I don't, I think they're very separate issues because we do have some experience, there was some vetting, there was FDA oversight and it was approved. So we have, I think, a lot more information about it. But I'll let some of the other folks weigh in. I think it depends a lot on what off-label use you're talking about. You know, for most of us as pediatrics, for many of us as pediatrics subspecialists, lots of medications are not approved for use in children. And as somebody who spends most of their outpatient time doing behavioral neurology, if I didn't use medications off-label, I wouldn't have much in my bag over the course of the day. So I think that's different. I think using something that's never been used in a given setting, because you think the biology underlying it might somehow make sense. That does get a little bit closer to what we're talking about here and that may require a degree of oversight. So I guess it depends on what kind of off-label use one is discussing before you would think about necessitating review at an institutional or department level from my perspective. Yeah, and I think Tina, this is Dave Williams. I think Tina may or Susan may want to comment on that. In some cases, off-label use does require the filing of an IND with the FDA. I think the off-label, I think the last number I heard maybe, David, you're on, you can comment is probably 70% of the prescriptions we write in pediatrics are off-label use of drugs that are primarily approved for adults. And I think that's a sorry indication of the fact that drugs are not studied well enough and systematically enough in pediatric age groups. And that's the reason, as you say, if we didn't have that ability, our ability to treat many patients would be severely curtailed. But I also agree with what Susan said, because this is somewhat different. These are therapies that have never been used in any human being before. And of course that when they're used in children that creates a much more, I think serious question about safety and efficacy as we've been talking about. Well, thank you everyone for your comments and folks in the audience for your questions. It's been a very rich and thought-provoking discussion that unfortunately is running out of time in our last couple of minutes. But I think it's also been a great illustration of the role of healthcare organizations, particularly the provider organizations that are heavily engaged in research as an organization like Boston Children's is. We're looking at ethical issues that arose really outside the scope of existing case by case governance. And those issues are prompting institutions to reexamine the direction that the field can take to benefit more children in the area of rare diseases and with implications for other situations that may arise as we think really outside the scope of conventional regulation and institutional oversight. Thank you for opening this up for our audience to think about and for our consortium as we try very much to highlight this kind of issue and see what continues to develop. So I wanna thank everyone for joining us this year and today and we look forward to further discussion in the next academic year. Thank you everybody.