 Welcome everybody. Thank you to everybody who has logged on so far. We're going to give people just another half a minute or so to to get connected. Right, I think, I think we are starting to see the majority of people who have signed up logged on although I think we'll continue to have people log on for the next few minutes but I think we'll get started because we have a great agenda for today and want to dive right in so Today we are. So I want to welcome everybody to the health policy and bioethics consortia research consortia series here at the Harvard Medical School Center for bioethics. My name is Aaron Kesselheim I'm a professor medicine at everyone's hospital and a faculty member at the Center for bioethics, and with my, my colleague Leah Rand. I help organize the health policy and bioethics consortia. And in a few minutes you'll be meeting our colleague in so he was well who organizes the the biotechnology and research consortium as well. Thanks, but that was a cameo from my son Leo. So, we are here today to talk about investigational drugs and stem cell treatments legal and ethical considerations of right to try laws, and our expert panelists I will also introduce in a minute. But I want to first of all just provide some technical insights that you know you can submit questions at any time using the q amp a feature. At the bottom of your screen, we will have time at the end to answer your questions, selected questions will be discussed, and you know feel free to continue the discussion on Twitter. We use the hashtags hashtag policy ethics and hashtag Harvard bioethics. If you have any technical issues use the chat feature and make sure to keep in. You know, to keep in the knowledge in the know about upcoming ethics events at the Center for bioethics. I'm going to go down at this website down here. Just to remind people who haven't joined us before the health policy bioethics consortium is a monthly consortium in which we bring in experts from around the country to to look at different perspectives on important issues at the intersection of health policy bioethics and the you know, describe some of the key ethical challenges in relating to the these policies or practices to bring together experts in particular who have different perspectives or experiences and to try to stimulate conversation and further academic study the field. And I just wanted to also give people a a bit of a preview for what's coming up on the policy ethics calendar for next year. We're going to be talking about confronting racism and disparities in health care. When we reconvene in February, we're going to take January off and then reconvene in February. After the inauguration, and in a different hopefully different political environment than we're in now. We're then going to be talking next about the next steps in health care reform to sort of leveraging this new political environment. And then in April, talking about care of prisoners before and during pandemics with some experts on that on that topic as well. So, if you're interested in these, please, you can go to the website of our group of Lee and my group portal, the portal research group at portal research.org, or you can check it out on the center for bioethics website. So for today's topic on investigational drugs and stem cell treatments I wanted to introduce, first our moderator in Sohyun, who's the director of research ethics and the senior lecturer at the center for bioethics at Harvard Medical School. He's also a professor of bioethics at Case Western Reserve University School of Medicine. Next, we will hear from Allison Bateman house, who's an assistant professor in the division of medical ethics at NYU Grossman School of Medicine, and she's the co chair, along with our Kaplan on the of the working group on compassionate use and pre approval access or CUPA I think she'll tell us a little bit about that. An academic group that studies ethical issues concerning access to investigational medical products that's composed of patient advocates clinicians lawyers FDA staffers and academics. She also serves as a non voting non paid chair of an end of a collaboration between NYU and Janssen called the compassionate use advisory committee for infectious diseases. The compact one a Reagan Udall Foundation Innovation Award for regulatory science innovations he's spoken and published extensively on non trial access to investigational drugs. And then finally, it's, I wanted to introduce George daily as our final speaker. Dr daily is the Dean of Harvard Medical School and the Caroline shields Walker professor of medicine at HMS. He's a leader in stem cell science and cancer biology. And in particular has been a principal figure as it relates to the discussion today in developing international guidelines for conducting stem cell research and clinical translation of stem cells. And this is part of the International Society of stem cell research, which is actually the forum in which Dean daily and I first met. So, I want to start with introducing our moderator in suit please take it away. So it's great to be here it's great to be the moderator for this exciting session, Aaron and I have joined forces and combining our two consortious I lead the consortium series on research ethics, and biotechnology. And this is basically launching to today's presentations, we're going to start with Dr Bateman house and then Dean daily will follow with his perspective, and we'll open it up for questions so when you have questions that you want to pose please put that into the Q&A box. And let's get started I'd love to hand it over now to Dr Bateman house, take it away. Thank you so much I just need to pull up my slides. Hopefully everyone can see that. Yes. So, thank you so much for inviting me here today and also for that gracious introduction. As was mentioned, I do co chair the compassionate use and pre approval access working group or Cooper. I also co chair a project called pediatric gene therapy and medical ethics working group or PG TME. So basically I spend most of my time talking about access to investigational medical products either inside of trials or outside of trials. And just to do my disclosures my salary support actually comes from a patient advocacy group parent project muscular dystrophy, as well as my home institution, my current project is supported by the WHO. I do run this project that was mentioned earlier in collaboration with Jansen, just want to point out that I'm unpaid for my work but the division receives funding from Jansen to administer these compassionate use advisory committees. I provide pro bono advice about access to unapproved medical products to basically everybody. Industry patient advocacy, non governmental organizations, government, etc. I don't accept funding. I do accept travel expense coverage from cost to 10 necessary things. And I serve on three data safety monitoring boards two of which oversee clinical trials involving convalescent plasma and you will see shortly why I felt the need to say that. So without further ado, let's talk about access to investigational medicines. So, you know, many of you I'm sure are familiar with historic events such as the thalidomide incident in which an unapproved product was used by pregnant women resulting in fetal harm. And incidents like this led to a requirement for pre market safety and efficacy testing of investigational medical products within our country. And the flip side of, of this, you know, requirement for trials that really give us confidence in the products that are brought to market is that during that time in which the products are going through the development process there's restricted access and for those who really have no currently available option for their medical concern who have all their hopes put on that investigational product and being able to reach it. This is obviously, you know, quite a concerning and troubling matter, particularly if you are one of the many people who cannot participate in a clinical trial for any number of reasons and we can talk about that during the Q&A. So, in designing this, this, you know, pre approval system, it was understood from the get go that they're going to be people who are therefore precluded from access to the things that they really want that you know might be in their medical best interest and this decision was made for non trial pre approval access. Now non trial pre approval access is sort of a wordy way of talking about what is frequently called compassionate use. I don't use that term I don't like that term we can talk about that during Q&A if you're interested but I'm going to be talking about non trial pre approval access. And the pathway that was created was something called expanded access, also known as EA I'll use them both interchangeably. And it's been in place since the 1970s it's been an ongoing process of evolution but it's here people use it. Thousands of people each year get access to medical products be those drugs devices, even vaccines outside of clinical trials through EA. And then more frequent more recently we have this new right to try act which, you know, lobbying for it really started around 2014. And it is still in a process of some evolution till today so I'm going to start with expanded access. You can't understand right to try without expanded access. So we're going to go through expanded access then into right to try and then up to right now when we're talking about you know pandemic situations. Expanded access expanded access that the watchword is flexibility expanded access can accommodate single patients it can accommodate groups of patients anywhere from two to you know some unspecified number. It also can accommodate widespread use of a product so this is after your phase three trial ends. You have evidence of safety and efficacy of a product but it's going to take a while for it to become commercially available and their patients who can't wait so you would use this widespread access provision of expanded access to enable you know even thousands of people to have access to your product. So let's talk about the cohort stuff today because we're talking about single patient because it's more analogous to right to try. So let's talk about expanded access for single patients. Again this allows clinical use of an unapproved drug, biologic or device. It's only for a patient who's in serious need and serious remember the watchword is flexibility serious is in the eye of the beholder. It's a serious need who has no approved options left to them and is unable to participate in a trial. You don't get to just say I don't want to be in a trial. It's that you are not eligible to be in a trial. There has to be determined that for this particular ratio. Sorry, patient, there's a positive risk benefit ratio for using this investigational product. The determination that allowing this expanded access use is not going to threaten enrollment of the trial trial enrollment is considered paramount over individual use. There has to be informed consent. There's an emergency provision for you know time sensitive situations where you can't go through the whole process. And there's real time reporting of unanticipated serious adverse events to FDA because these are products in development. And if there's a safety signal or something that hasn't been seen before, FDA is going to want to know that about the product. So the actual process just to do this very quickly for anyone on the webinar who has not done this before you have to identify a willing physician physicians do not have to do this so if you're a patient that wants to do this you have to find a physician willing to do expanded access with you. Or if it's the physician who who you know is the one who generates this idea, there has to be this, you know, agreement between the physician and the patient that you want to do this, the physician or the patient has to identify a promising product. And then it has to be the physician at this point in all the all the responsibility shifts off the patient to the physician. The physician the physician contacts the sponsor to explain what it is they want, why why the patient patient isn't eligible for clinical trials. And it's up to the sponsor to say yes or no there is no legal requirement for a sponsor to say yes and sponsors. Some of them say yes quite frequently some of them say no, almost always some of them, it's a mix so it's really up to the sponsor to decide if the sponsor says yes, it helps the physician complete a form for the FDA. It's a short form. The FDA reviews the form and decides whether this procedure can go forward or not. And if the FDA says yes the last step in this process is that the physician has to seek IRB approval. It's not an unapproved product, it's not a clinical trial but it's still an unapproved product so we want to make sure that there's, you know true informed consent patients understand of any conflicts of interest etc, which is the role of the IRB. There's lots of claims out there about expanded access, many of which are wrong so I just want to fax fact check briefly here. One of the largest misconceptions is that the FDA often says no to these requests, and that's not true. As a public agency all of its numbers are public. You can look and see that thousands of patients each year get access through FDA. Now what we don't know is how many patients initially went to sponsors with request and the sponsors said no. That's a black box we don't have any idea but we know the FDA over 90% of the time says yes. Next claim FDA is too slow. Again, no, although with the caveat you know what is too slow is in the eye of the beholder but we know FDA turns these things around very rapidly. And indeed for the emergency use provision can do it same day. So it's quite fast. It takes too much physician time. Yes, I would say that that is a true problem with expanded access, but it's not the FDA paperwork. I mentioned earlier that the sponsor helps the physician fill out the FDA paperwork. That form is estimated to take about 45 minutes. What frequently physicians get bogged down in is the sponsor has additional paperwork and or the institution has additional paperwork so you end up having paperwork from lots of different entities that you have to deal with and that's really one area that needs to be targeted for streamlining. And then the big one patients are denied access, and this goes back up to the first one I had which is FDA often says no, FDA does not often say no, but companies may indeed be the ones saying no. And that's where you end up with situations like this where you know a family is petitioning trying to get public support for access for a product that a company has already said no to. Now those sort of misperceptions and myths about the FDA when it comes to expanded access were fertile ground for something called the right to try so we're transitioning now to the right to try law. This was a legislative initiative put forth by the Goldwater Institute which is a libertarian organization. And the thrust of this is explained very aptly by the subtitle of this book by the former president of the Goldwater Institute, how the federal government prevents Americans from getting the life saving treatments they need. And when they say federal government they need, they mean FDA so basically the right to try premise is that the FDA is blocking patients from getting access to something that they both want and deserve. And that, you know, in order to allow patients to have this access you need to diminish the role of the FDA. I can tell you right now it was just a misunderstood or even false claim from the get go patients don't get access because of company decisions it's okay but nonetheless, we're in an era where facts don't necessarily matter, especially when it comes to legislation and so, you know, a campaign to have state right to try laws was incredibly successful bipartisan. And as you can see on this map made by my colleague Lisa Kerns the shaded states all have right to try state laws on the books these are all unique laws it's, it's really difficult to keep a track of all of them because they're actually still in evolution trying to figure out, you know what provision got added this legislative session, etc. I think the real important thing to keep in mind here is that these are, I'm going to say legally suspect and we can come back to that at the q amp a I'm going to go back and engage with someone who actually is to explain this but these laws are on the book they're not really being used because they're questionable legality. So let's talk instead about the federal law of which there is one that passed in 2018. If you look at this slide, all the text in white is things that I copied over from expanded access and the text in blue is what I have changed to show you that really right to try is like expanded access light. It's, it's less flexible, and then it diminishes the role of the FDA. So let's go through the, the, you know, sort of qualifications first so that you can see it's less flexible. It still allows clinical use of an unapproved drug or biologic it does not allow use of devices, and there's now a restriction there rather than that drug or biologic being at any point in the development process. It has to have successfully completed a phase one trial. This is frequently called a safety trial I don't like that terminology I would say more like pharmacokinetic and dose finding trial. It's still in development under FDA auspices. So, restricting what products are available through right to try only for single patients you can't do a group here. Not for serious need anymore now for life threatening need, of course how exactly life threatening need is defined as somewhat nebulous but still a restriction still positive risk benefit ratio. There's no provision that it not threaten the trial still informed consent although you can see a little asterisk there because the provision of what is required and informed consent is much lower than what is required and expanded access. There is no emergency provision and last but not least you can see instead of serious adverse events being reported to the FDA in real time, they're only reported annually. And there's actually a provision that the FDA cannot use these reports in its regulatory decision making so it can't penalize a company for for these safety reports. There's, you know, sort of some parisos to that we can talk about during the Q&A. And in terms of process you can see it's it's much shorter you just have to have a willing physician a willing patient and a sponsor who says yes the FDA is cut out. The IRB is cut out although you can see I have an asterisk there again. That's because some institutions have taken it upon themselves saying if it's happening on our campus we want the IRB involved. So if you're going to be right to try on this campus it has to have IRB approval, and also some companies have said the same thing about, you know, if we're going to use right to try there has to be an IRB sign off so that the IRB is not in the law, but in practice it is still being used in some context, although I should bracket that and say the right to try law is being used very very very infrequently so when I say some places are setting this proviso into place it's more you know they're writing that into their policy as opposed to it's actually happening. Now we knew from the get go that this law was not going to be effective in increasing patient access to drugs. Here's a newspaper article from 2015 so three years before the federal law was passed and it encapsulates the problem right here. My dad had hoped for the first time since diagnosed with ALS when he found out Missouri was a right to try state. He thought that because he was moving back to Missouri he could try this drug. The company however refused to provide it. And this gets to the heart of why many people including me were concerned about right to try. You know, we said it offered false hope because you tell people that they have a right to something which the only right they have is the ability to ask for something and of course they've had that since the 1970s there's nothing new here. But if you look at that final paragraph, can you imagine the hope we felt this entire process puts the most emotional time in our lives on an even more emotional roller coaster. So there's nothing here to convince companies to give access where they hadn't already been willing to give access and that was clearly predictable. And so now we're in a situation where instead of having one pathway to non trial for approval access we have to companies who didn't want to give access still are not giving access and there doesn't really seem to be any significant change in the volume of patients who are getting access, either through expanded access or right to try it really seems that it did not make a difference. That being said, there have been lots of positive changes I'd be happy to talk about that during the Q&A just in terms of like transparency of policies, etc but no real change in numbers. The number of patients who you know their their impetus was increasing patient access the numbers are what really matters. And I also just need to note here that we have very imperfect insight into the numbers. I mentioned that things that go through expanded access the FDA keeps track. There's no currently central register of right to try so you really have to like read news reports and whatnot to try to find examples of that. Even for those FDA numbers. There's no distinction between the group and the individual in terms of actually keeping track of numbers. So for the FDA's purposes, you have a one, whether that means one patient or one protocol that has a thousand patients so it's very hard to keep track. Moving on a little bit this was a project that my co authors Jeremy Snyder Lee Turner and I just did and just had published trying to figure out you know this question of is right to try being used as I said there's currently no central register. Eventually at some point companies have to start doing that annual report of serious adverse events but that hasn't gone into effect yet. So what we thought is we thought, you know these are unapproved experimental drugs, many insurance companies are not going to pay for them. And so, unless you have someone who is able to pay for it out of pocket, you might have people who are on go fund me or other crowdfunding websites saying, you know I want to do this but I need help to do it. Because even if a company provides their unapproved product for free, which frequently happens, there are all sorts of ancillary cost you have to travel to a site. You know you have to have an imaging scan or you have to have lab work or something that people can't afford to pay out of pocket once their insurers says they're not involved so we hypothesize that whereas it wasn't perfect this was a proxy we could see for it was right to try being used. But the answer was we saw people who had gotten access to an unapproved product, and we're just trying to fund the ability to use it. They were using expanded access. We did see people frequently talking about right to try, but it was really not in terms of an actual pathway that they're using but more this sentiment of I should be able to get this thing. We saw it for unapproved products we saw it for approved products where you know maybe the insurer wasn't paying for them to get, you know this approved product and they were trying to crowdfund the cost of it and use sort of the right to try ideology to support it. And also things like you know I can't get this, you know stem cell infusion or whatever in the United States I have to go to Mexico to get it. You know it's my right to try to be able to do this but I need people to fund my trip to Mexico in a medical tourism so it really was used much more in a in a you know sort of symbolic fashion than an actual legal or regulatory one. One of the most frequent uses you'll see a people talking about right to try use is this woman Natalie harp, who said that you know she had a cancer she is now alive today due to right to try actually actually spoke at the Republican National Convention. And this was not an example of right to try right to try just to remind you is limited to unapproved drugs, and what she used was an approved drug for a different purpose than what it had been approved for. This is called off label drug use it happens incredibly often. It has nothing to do with right to try in terms of the law, but of course it might share, you know this mindset of I should be able to try whatever I want regardless of whether the FDA approved it for that purpose or Now, just to you know bring us up to present date. How, how does this mindset or how do these laws interact when you have epidemics. So just to give you the good news first, and we can talk about this during q amp a if you're interested. There was quite a lot of investigational interventions used outside of clinical trials for the Ebola virus disease. There is a protocol from the World Health Organization called neary or monitored emergency use of unregistered and investigational interventions. I actually think that this was a really good example of how you can use non trial access in an epidemic can talk about it during the q amp a it wasn't perfect but I think it was pretty good. And I think by that lead in you can probably guess that I'm going to say I don't think what's been happening in coven at least in the United States has been particularly good so we had the good example now we have sort of the ugly example. For people who haven't seen this article in the New York Times magazine. I really strongly recommended it's the best piece I've seen to date. And you can see here how much freedom should frontline clinicians have in treating coven patients with unproven drugs. So whether the drug is available, you know, it's unproven for coven 19 but it might be off label. It's an approved drug for some other purpose, or whether it's made available for an emergency use authorization or whatever it is. Should clinicians use things that they think might be in their patients best interest or should they really prioritize putting patients into the clinical trials where you'll get the safety and efficacy data that would be useful for the larger population I strongly recommend this article. So let's talk about it in coven 19 in the United States I have found no uses of right to try. So, I'm not a big fan of right to try I think it's vulnerable to abuse so for me that's a good thing. Expanded access during coven 19 we've seen massive use of it and so the question is has it been used appropriately or has it been misused. And I think probably both I think there probably has been appropriate use and misuse but I just want to flag one or two examples for you. So this is the convalescent plasma expanded access program which I think many people have probably heard about and if you look down at the bottom I circled that over 92,000 people got access to convalescent plasma outside of a clinical trial through expanded access. Remember one of the rules of expanded access is that it can't interfere with trial enrollment and remember all the way back at the disclosures I told you that I am on a DS and be for multiple convalescent plasma trials. I can tell you trials for convalescent plasma they're not accruing, they're not enrolling the numbers of patients they need and when you look at this sort of non trial access to convalescent plasma that's no real surprise who wants to go into a trial when you can get it outside of a trial. You know in the trial you're going to be randomized potentially to placebo outside of the trial if you want it you're going to get it so I really think that this is like a staggeringly huge number for expanded access I've never seen anything comparable. And it does make me think that it probably crossed that line between, you know, appropriate use of expanded access versus interference with trials. Next example, I think everyone is aware that President Trump used expanded access to get access to an unapproved drug, as well as some other high placed political allies of his. And these may or may not have been appropriate uses of expanded access but it really has you know sort of gendered up this concern that there's differential access for the wealthy and the powerful as compared to just you know that the everyday person. And then I think most people are aware that there was this idea of, you know, setting aside expanded access and turning to right to try that you had a right to try hydroxychloroquine or whatever drug you wanted for coded 19. And I think I don't need to belabor this point I've already talked about what off label use is this was off label uses had nothing to do with the right to try law and everything to do with the right to try audiology of I don't care that there's a trial going on right now I want it. I deserve it, I should have it. So in the last few minutes, I'm just going to transition away from the pandemic into a couple other current situations where we see the sort of right to try language being used. And so, one, this is something where it's not right to try or expanded access eligible. This is a case that I found in the Milwaukee Journal Sentinel of a man who is selling a $1,800 a month, quote unquote cure this is a supplement. It's not eligible for right to try or expanded access because it's never entered the FDA developmental pathway. You know, you can't use those pathways for things that are just completely outside of FDA auspices. But that's what this is and he claims that he can legally sell it to cancer patients because of the right to try act. That's just fraudulent. It's false, but it's out there. And here's one that's really interesting. I'm sure some people have seen people saying well now we have a right to try, you know these controlled substances psychedelics mushrooms LSD ecstasy. And the, the very brief answer to that is, you know, if you can find those products from an actual FDA regulated sponsor, and it fits all the other criteria of right to try or expanded access. They are eligible, but simply because say for example you get psilocybin from an approved sponsor and it's eligible for expanded access that doesn't mean you can go buy it on the street corner and say that you know through expanded access or right to try you're using this in accordance with the law it doesn't work that way it's much more restrained. So here's my conclusions. The preferred route of access to investigational products is always clinical trials, but not everyone's able to participate in clinical trials. That's why we have these non trial pre approval access pathways, the federal right to try law is restrictive and it's not being used much for its intended purposes, the expanded access not as restricted. It is being used as intended, but it also seems like it's being used outside of that intended scope a bit and I think we need to sort of pull that back in the right to try ideology per fate pervades you know not only seeking access to unapproved medical products but all sorts of things. You know the, the, the control drugs like psilocybin, you know, approved medical products off label whatever it is and and I have a hypothesis here that I've been kicking around with my colleagues that this might be related to this shift in medicine over time from you know the patient as as a recipient of the physician's wisdom to really the patient as sort of the consumer who gets to decide what they're getting so we can talk about that during the Q&A. And then I just want to flag my really overwhelming concern that you know by having these sort of one off treatment decisions where you prioritize what the patient wants when they want it. We are jeopardizing our societal need for evidence and for some people that's a reasonable trade off and for others, including me, that's that's a really risky trade off to make. So I will end there. I just like to thank my colleagues who talk about this stuff nonstop with me and I'll turn it over to George. Thanks so much Dr Bateman house I was a fantastic presentation extremely concise and informative it sets us well up for the next presentation by Dr. George daily. So, Dr daily I'd like to get your perspective on these issues. And I'll turn it over to you. Well thanks ensue. Let me pull up my slides here and just make a few introductory comments. I am. First of all, thank you ensue and Aaron for inviting me I'm part of this forum. I was just riveted by talk. I have much to learn here and that was extremely informative. I'm sorry because of my long history with the International Society for stem cell research and writing international guidelines where a professor he was a close collaborator and colleague over the last 1516 years. We've had several generations of guidelines that speak to the conduct of human stem cell research but importantly for this conversation for the clinical translation of that research and I think it's clear that the history of stem cell therapies illustrates the kind of risks and burdens that are presented when a very promising new area of biomedicine sees premature clinical uses of therapies before they're proven safe and effective. And the rise of stem cell clinics, which we know pedal snake oil largely has really led me and many of my colleagues in the ISSCR to believe the sort of latest strategies. Really the negative consequences of right to try legislation really overwhelms any potential value and those burdens include the potential for exploitation of patients, often when they are at their most vulnerable. And as Allison left us with that last bullet point, it undermines the pursuit of legitimate evidence in the establishment of the safety and efficacy of treatments and that is a very significant societal burden so once again as we've seen with many of the more recent political squabbles, we're really pitting this so-called ascension of the individual and the individual rights against what is really in the better interest of the broader society and the broader community. So I'm just going to walk a little bit through the history that we have witnessed in the stem cell era and hopefully make it relevant to this right to try discussion. Now that history arguably can be traced to the late 1600s with the first attempt at blood transfusions it was clear for millennia that hemorrhage would be a rapid form of demise. And there were various experimental strategies and in 1667 is written up in the philosophical transaction there was a Mr. Arthur Koga who was infused with lambs blood. Now, this was not for simple hemorrhage but rather to treat what was likely a syphilitic mania and as you can imagine, this hapless gentleman Mr. Koga died sometime later. But this really says to us that we've had centuries of unproven interventions in medicine. Now it really has to, one has to acknowledge that the path to the establishment of safe and effective medicines is very long and arduous and it's exceedingly prone to failure. And indeed when you think about entities whether they be drugs or, or biologics. When they enter the regulatory process in phase one there's a tremendous winnowing, and the failure rate is really predominant. It was always traditionally quoted as about a nine to 10% chance that any product entering clinical development would ever get approved. That's been slightly sort of the estimates have increased recently there was a paper in 2018 which said it was up to 14% perhaps we're getting slightly better at the regulatory process. But even once drugs are approved. There's a very significant number that end up being withdrawn, only after they have been marketed and widely widely used, not in just the, you know, hundreds to thousands of individuals who enroll and are the substance of trials but into the hundreds of thousands or millions of individuals in the marketing phase and this should give us pause as we think about the promise of the vaccines that are going to be winning emergency use approval. There's an emergency use authorization in the next, you know, week or so that we might expect and in fact we've already heard some early returns of adverse events allergic reactions in the vaccination campaign in the UK. That's hard. It's hard to get a safe and effective medication. And the bedrock principles on which biomedicine rests include the importance of conducting rent when where possible, randomized clinical trials that are blinded in the assessment of those data represent the highest and most reliable form from of evidence that allows us to conclude the safety and efficacy of medications. The problem with right to try in the theme that I'll return to is that it really celebrates and legitimizes anecdotal accounts of success, and we know from a long long history of medical judgment that anecdote is not a good way to define safety and efficacy. Many of you will remember that the very, very distinguished drug company Merck introduced a whole new class of painkillers. The so-called Cox two inhibitors Vioxx among them. And this was supposed to be a transformative safer form of pain relief, but even in the best of circumstances, with a company as storied as Merck, only after these cases. Sorry, only after approval, did we find the negative side effects of this of this drug that led to its withdrawal from the market. So even in the best of circumstances, we can be fraught with error and risk and manufacturing alone carries with it its own set of risks. As we learned recently here in New England with an outbreak of fungal contamination for steroid injections which had been put together by a compounding pharmacy that in any attempt when we are treating a patient and breaking the skin introducing a medication that we carry the risk of potentially life threatening infection. But when you're a patient and especially when you're a patient facing death, where modern medicine doesn't have the possibility of cure, where do you go to find out about potential treatments including all of the hype around stem cells will you just simply Google. And I recently googled again stem cells cure for Alzheimer's disease. And unlike a few years ago when this would have turned up a whole series of advertisements supporting unproven stem cell interventions. Actually, there's now more legitimate information available here we see from the National Institutes of Health, or European stem cell organization, but you don't have to go too far down that first page. Before you see once again, an advertisement of a stem cell therapy for Alzheimer's offered by the DVC stem cell company. This is a company that operates in the Cayman Islands. And indeed, it has photographs on of, you know, PPE clad physicians, it has the veneer of medical respectability, but one of the real red flags that tells us that this is likely highly illegitimate is that we know this is an unproven intervention, and yet it's carrying a $20,000 price tag. Clearly, patients are at risk of financial exploitation, if not the risks of an unproven therapy. There has been a growing direct consumer industry that has grown up around stem cell is stem cell treatments. And the problem is that we have an area of biomedicine, which is novel, has enormous promise, and perhaps has been subject to the significant amount of overhyping. The clinical use of this promise is been premature, and it's gotten ahead of the science. And the marketing of these unproven interventions prior to a consensus about safety and advocacy is occurring, and typically has been outside of FDA regulation. Fortunately, Scott Gottlieb most recently when he was FDA commissioner actually stepped forward to try to use the regulatory authority of the FDA to shut down much of this practice. But what we're really talking about is a clash of cultures as well. Stem cell therapy is a medical innovation. It's often considered in some instances, especially for the autologous use of one's own cells as sort of falling outside regulatory of the FDA, although this has been challenged by the FDA. And it also can be caught up in these arguments that are often used that somehow the medical community is acting to be conservative and orthodox research is standing in the way of patients finding cures. And indeed, as we've seen the right to try regulation is really set up as a counterweight to the perceptions of an overbearing regulatory paternalism from the FDA. Now there are risks, and those risks are now increasingly being documented in the medical literature. Here was one of the early reports now over a decade ago of a young Israeli patient who traveled to Russia to receive an unproven intervention essentially in infusion of an ill-defined slurry of what were thought to be neural stem cells, but it was really a slurry of fetal forebrain. And unfortunately, this child developed tumors in his central nervous system, as was reported. Recently in the New England Journal of Medicine, a couple of cases of individuals receiving direct intravitrial injections of so-called safe autologous stem cells to treat their macular degeneration, each of them suffering significant visual loss. And I came across recently a paper from 2018, which is a very comprehensive review of the very large number of now well-documented cases of adverse events, including death from the interventions with stem cell treatments that were unproven. And indeed, there's even a larger number of media accounts that have never made their way into the medical literature. So again, on behalf of the International Society for Stem Cell Research, we have worked really diligently to try to provide proper education to individuals about the challenges of clinical translation. And there's a website called a closer look at stem cell therapies that we ask patients who are considering these kinds of unproven interventions to consult. It arms you with the kinds of questions one needs to ask of their clinicians, many of whom are not always physicians, certainly not expert physicians. What is the evidence base for the intervention that's being considered? What is the rationalization for payments for such interventions? And when one starts asking the tough questions, it becomes pretty clear pretty quickly that you can distinguish these illegitimate snake oil salesmen from more legitimate clinical trial development. And the CR has spoken out very aggressively against the marketing of these unproven stem cell treatments and is on record as opposing the right to try legislation that we've just heard so carefully discussed by Allison. So just to sum up, I often like to say, if it's a right to try, it's also a right to exploit. And that these mechanisms have actually been driven in large part by companies that are in fact peddling these unproven stem cell interventions. There has been a close connection between the lobbying efforts for this legislation and such companies. It is in general, enabling a premature use of an unproven treatment. A treatment that if even under the proviso that they have to have satisfied at least a phase one clinical trial, which is often predicated at least partially on establishing safety. Absolutely no doubt that significant safety concerns as I pointed out earlier in my talk, only surface in larger, larger populations of patients, and even after a regulatory approval leads to withdrawal of drugs in a significant percentage of cases. I think it's also important and perhaps we'll discuss a bit in the question and answer is that these right to try is often founded on a therapeutic misconception that is a excessive expectation that these interventions are going to prove effective. And that has a really corrosive effect on informed consent. And of course, we're often said, Well, what do we have to lose. Why don't I have a right to try. Well, the fact is, is that interventions can hasten death and exacerbate suffering. And among the other things that one stands to lose and in addition to money, if you will, are the access to more legitimate treatments. And by perpetuating a false hope for cure. Oftentimes, these efforts to gather this right to try delays the otherwise natural progression towards an acceptance of one's fate. And this can deprive individuals in their families of a compassionate reckoning with the end of life. So as I was pointed out by Allison undermines FDA oversight of experimental treatment, and I fully fully concur that it erodes the importance of rigorous standards of evidence based approvals. And it legitimizes and promotes anecdotal and selective support for experimental therapies. And that ultimately is, I think, a very, very detrimental impact on the, the, the regulatory process for approving new therapies which as I said from the beginning is a long and arduous task but there is no easy way forward. So thank you very much and I will stop my screen share and look forward to taking some questions with Allison. Thank you Dean daily that was terrific it was a great way to dovetail from the end of Allison's presentation and then get us into the Q&A. So while I compile and sort of organize the questions that have come in let me just start off with just an overarching question for the two panelists. I think that an overarching theme that I heard from both your presentations was this distinction between right to try as a law or policy and right to try as an ideology. And I'm really fascinated by the right to try as an ideology. I can both of you speak to that issue. I mean, clearly there's an unmet need here amongst patients who, who espouse or who follow this right to try ideology. And Dean daily, I was intrigued by your whatever last comments you said that sometimes these, you know, hurried attempts to seeking last Hail Mary cures, the latest ones reckoning with end of life, and, and the real matters that are ahead of them. So could either could both of you speak to that issue of what do you think is sort of behind this, what seems to be an unmet need or a great interest in right to try ideology and what could be done to address that. Yeah. Sue, let me, let me invoke one of, I think you're most compelling written commentaries on that issue. And we, I've taught this in an undergraduate class that I've taught in for more than a decade. And that is recognizing the fact that patients are not well served by modern medicine in many aspects of addressing their spiritual needs, and that the the right to try ideology is really about satisfying that yearning for hope. You've written about it as an issue of spiritual distress that somehow we in medicine need to recognize the importance of the pain and suffering and spiritual sense that the patients need, need, need addressing. Another work that I think speaks to this is the, the book by Jerry Grootman called the anatomy of hope where he draws a distinction between the false hope that is provided by the snake oil salesman and that the right to try legislation really buys into true hope, which is what the best physicians offer to a patient. You know, I am trained as a hematologist oncologist and have had to have difficult conversations, conveying tragic prognoses to patients with terminal cancer. And yet, you never as an oncologist walk away from a patient, you never offer them false hope, you offer them comfort, you offer them solace. And that is a critical part of addressing that spiritual distress that I think is what drives a lot of these alternative strategies and ultimately this right to try ideology. Thank you Dean Daly. I didn't mean to fish around for a plug of my own work but thank you for that. Very germane it's central to the, to the, to the issue we're discussing absolutely. Thank you. I just want to add one thing on to that I don't, I don't disagree with anything that George just said but I want to go back to a word that he said during his presentation that I think is key, and it's anecdote. So I think that patients, particularly patients who don't have a medical or scientific background are suddenly thrust into the world of I have a disease, and I have to deal with understanding what I'm supposed to do or what, what seems reasonable and what doesn't seem reasonable. And it's really, really, really hard for someone particularly a layperson who has no previous experience with this disease or condition to understand what is a, you know, a validated thing that I really should put my eggs in that basket versus what is not. You know, I'll point out I'm an ethicist I'm not a physician during COVID-19, where every day you had a data dump from some other place and some of them were, you know, RCTs but you know perhaps underpowered and some of them were great, great powered RCTs and some of them were observational. I mean, I was struggling trying to figure out which one of these do I put my faith in. And, you know, I'm someone who spends my life looking at access to investigational medicine so I can totally sympathize with someone who says, This is not my world at all I'm just trying to figure things out and I heard this story about somebody who said it works for them and so I'm going to go for it. I think as a medical profession, clinicians have to do a better job of helping patients on, you know, vet out what's a good source of information versus what isn't and that's what George is saying that the stem cell world is trying to do. And I just think it's crucial. Okay, so I'm going to turn to some questions that have come in there's one that's come in from an anonymous and attendee but I'm going to, before I ask this question I'm going to sort of preface it with another question of my own and that leads into the attendees question this is for Dr. So, my leading question is, it's odd that the federal right to try legislation is actually more restrictive in some ways that expanded access. So, could you speak a little bit to why you think they went more restrictive you would have thought they would have gone much more liberal in many respects, especially for patients. You know, facing many different kinds of conditions not just a fatal ones. And that leads into the attendees question which is what are some of the common reasons why the companies would say no, in both cases of you know RTT and the expanded access. So let me start with the second half first and then I'll lead back into it so a common reason a company would say no to write to try and keep in mind in two plus years of this law being on the books my group has found less than 10 uses of it, it is not being used. And I think the main reason that a company is not choosing to use right to try is a they don't see it offering any advantages that they don't get already from expanded access. And to, you know their end game is to bring a drug to market through the FDA and it sort of sets up an oppositional tone to be like, you know, oh but in the meantime we're going to give access to patients and cut you out of it. And I just think strategically companies have no reason to go the right to try route. I'm only aware of one company that's doing it routinely through right to try and I mean I really have serious concerns about that company because I think it is telling about their attitude. That's why a company would say no to write to try a company would say no to expanded access for many reasons but they really boil down to two one is, we are not comfortable giving our drug to people or device to people outside of a constrained trial setting yet we think they need monitoring well like we're just not confident handing it out to people yet. I think that's a very reasonable reason to say no. Probably the second most common reason to say no is just it takes resources. I mean these are not free of cost and if you're not passing the cost on to the patient, somebody has to absorb those costs. So companies, particularly small companies that have no revenue. I mean it's just a drain on their resources and they somehow have to justify to their board or shareholders this is why we're diverting our attention away from clinical trials which in the long run are going to help more people and bring the drug to market faster to take care of the and you know in some cases you can make that argument if you have a, you know, a devastating rapidly progressive disease. It would be, you know, like, yeah, we can understand why you would set, you know, x% of your, your supply aside and take care of these immediate needs because these patients will not survive to be part of your, your client client tell pool down the line but I think in many cases it's a challenging right to hoe. And now of course I've forgotten the first part remind me the first part. Why did they go more restrictive with breakfast. Oh, so, so we don't want to bore anyone to death but I mean this literally was like, you know, a soap opera that I unfortunately followed every last step of it I think it was very much real a real politic of what do we think is actually going to get to be law. So, I mean I think, ideally they would have had a much more expansive thing and just thought, you know, in order to get any sort of backing from this, we have to narrow it the one place where you'll notice they didn't narrow it was on the serious adverse event reports and the serious adverse event reporting you know if you were narrowing, then you would have kept that you know we're going to have real time reporting of serious adverse events to FDA and instead they threw that out completely and said, it's only going to be a once a year thing and they can't use it for regulatory purposes and the idea there. And there was some justification to this so it was an interesting exercise was that companies are saying no, because they are afraid that if something bad happens the FDA is using it against them and so you have to take that you know sort of tendrance away and then companies will feel more free to get access I think we can say now that that has not worked out but it was an interesting idea. Allison I'm, I'm, I guess I'm intrigued but somewhat reassured that you know the legislation is actually not getting used. So, as you point out, I think it was Alta Charo who called, called it placebo legislation. Right, I mean it sort of makes, makes lawmakers feel good and and jins up some of the base but doesn't really have a major impact. So let's say without saying who the legislature was we are great pad of conversation with a legislator saying, you know, as, as you just said like this is feel good legislation but it's not going to change anything for anybody and if it does change, it's going to be a negative change because you're taking some of the protections from, you know manipulation and, and, you know, misuse away from patients, and this legislator who will go unnamed was like, Yeah, but nobody except for you and I are really going to vote for that. And when people go to vote for me in office they're going to see I voted for right to try. Okay, great. I have a question here from an attendee. So theoretically all those participants who get the convalescent plasma, they would actually be ineligible for trial. So trial recruitment shouldn't have been affected by those folks who would be responsible for ensuring the patients who are ineligible for trials, get something like convalescent plasma. So that's actually a really interesting point and I may respond by saying, this is like sort of the pandemic exceptionalism. Normally what we do is we have an oncology trial or we have a stem cell trial or something. A patient comes along wants to get in they can't get in and then they go well is there some way other than this trial I can get access. In this case the trials were being created in real time. So it wasn't that the people were ineligible for a pre existing trial. It's that the trial was being created right then and there weren't enough people for it, because they were already being treated. I mean this is happening in real time. And when you talk to, when you talk to clinicians or when you talk to a hospital administrators or something. They say, you know, yeah, we have massive amount of convalescent plasma use, but it's all going through EA we just don't think that there's enough where with all to set up a trial here and trials take money and they take time and they take effort and, you know, particularly if you're a small community hospital, you can just say I don't think the trial is going to happen so it wasn't that it was diverting people away from existing trial it was really diminishing the need, the desire to start up that trial from the get go. And then getting away from convalescent plasma the other question about who's in charge of making sure the person truly isn't eligible, theoretically it's dispersed you know it's the physician's job to make sure that really this patient isn't eligible for trials. Then it's the sponsors job really to make sure when they get this request, they don't say you know why aren't they in our trial. And I just want to point out it doesn't have to be a biomedical reason why they can't be in the trial. The trial can be in Boston and the person can be a Wisconsin and you can say it's just like not feasible for this. So, you know, they're there various reasons why you can't get into a trial, but but so the sponsor should be checking that the FDA also should be checking that should be saying you know like this looks like a trial eligible patient why aren't they going through trial. Last but not least the IRB should be doing that although honestly I think at that point they're probably the ones who are least set up to be able to really evaluate that in any meaningful way. So the responsibility really rest on the physician the sponsor and the FDA. Terrific. So I have a question for Dean daily. So clearly physicians have a pretty major role in exercising their own judgment in these kinds of situations. Do you think there are standards for professional medical professionalism that come to bear here and you know what is there, for example at Harvard Medical School or students kind of given any kind of resources or ways to think through these kinds of future decision making that they may be engaged in. Well, let me yeah. So what are the constraints on professional practice. So we are held to very, very high standards. They are quote community standards but given that community is now accessible if you will and generalizable with access to the internet and the growth of telemedicine. So general physicians across the globe are going to increasingly be held to the highest standards and aren't going to be able to just get away with sort of shooting from the hip, we're going to have to base our best judgments of clinical care on all of the accessible information which is really quite voluminous. Our medical students, I am very, very, I'm encouraged because we have enriched the curriculum with a heavy emphasis on professionalism, the practice principles and bioethics. And so, you know, whereas we don't necessarily teach tort principles and the like, but all of our medical students are made aware of the importance of, you know, evidence based interventions evidence based decision making. They're taught about the regulatory process for drugs the use of off label. And I think they're given exposure to and and some achieve real mastery of the principles of bioethics, and the importance of informed consent of, you know, for patients, especially if they're receiving experimental types of treatments. I think we're asking an awful lot more of our medical students today. Thankfully, then I recall being asked when I was a student I had to learn much of the many of these principles, along the way on the job, if you will but I'm, I'm, I'm encouraged to think that our medical students are getting are getting a very enriched sense of the social context and the ethical context of the practice of medicine. Terrific so Dean daily you mentioned informed consent and this leads me to a question now for Dr Bateman house the questions come in. How is informed consensus. How is informed consensus filled with drugs or biologicals given restrictions imposed by proprietary considerations and I think this is being asked in the context of expanded access. So, I mean one thing you have to keep in mind is the, the informed consent piece is sort of handed over to the IRB to handle right and the IRB as I've already said comes at the end of this chain of sign off so a couple years ago we did a survey of IRB is nationwide to see do they ever say no, you know if a sponsor signs off on something and the FDA spine signs off on something and the physicians behind it would an IRB ever say no and we found literally like maybe three cases so I don't think that that's a very robust informed consent process I personally would want to alter it to make it more robust. But I mean that down to the practicalities of if you have proprietary information what do you put in the informed consent. When I advise companies I tell them basically to take your clinical trial informed consent, cut out all the stuff about randomization or long term follow up or whatever and just get to the nuts and bolts of what is the drug what is, you know the perceived benefits the possible risk and use that as your informed consent document. Some companies will actually send an informed consent template along, you know, to the IRB others, you know they just sort of like make it up so there's real inconsistency there but I think you generally use the trial document as your guide. Great. Another question is coming in, I think this is for both of you. Is there or has there been any follow up on the non trial use of convalescent plasma. I'm not sure what you mean by the follow up so so I mean it was a massive program and that data was published as a as an observational study. They actually tried to do some internal randomization by you know tighter of of and I'm the non physician here. I think that's what it's called tried to do some like you know pseudo clustering of that to see if there was, you know, a determinant of impact and came up with some conclusions that's all been published in the literature. But I mean I really think until we have the RCT is done it's not strong enough evidence to base. In my opinion treatment plans on. I'll defer to the dean though because I'm not a physician. I know Allison I think that's right they didn't do randomization but they did some, you know, post hoc observational analyses to try to draw some conclusions but you know the, the, the, the experience was necessarily sort of first come first serve because it was under an expanded access program it wasn't part of a controlled trial. Erin thanks for to for correcting my terminology but yeah so post hoc analysis trying to say that they saw a signal towards efficacy but I just don't think we can take that as gospel yet. We've seen a evolution in our thinking about interventions throughout the coven pandemic, obviously in the early phases of the pandemic. As sick as patients who were being treated with convalescent plasma with remdesivir and the like. And we were, in fact, probably over encouraged by anecdote and as one of the, one of the attendees has has said the plural of anecdote is not data. We really need data and so what we saw was the establishment of randomized clinical trials testing, testing, convalescent plasma remdesivir and hydroxychloroquine and steroids and all of that. And we came to the sobering reality that those probably weren't working. And yet we also knew that from from evidence and treatments of other respiratory illnesses. There was a lot of hammer flu for flu that these are interventions that typically are only effective if they're instituted early in the course of infection so that they can disrupt the spread of the virus within the individual so I think we're now starting to see. In part the hypothesis stimulated by these post hoc analysis of the aerial trials, leading to now earlier stage intervention still done in a randomized context so that we can get reliable data. And I think you're going to see these interventions moving earlier earlier in the treatment of our patients. So I just want to say for a second I think one of the things that we need to take away from the COVID experience is you know what are our learnings I mean obviously, you know trying to get clinical RCT is up and running early is a learning but but I would just want to say specifically, it's hard to expanded access the FDA quite frequently when it sees a series of single patient requests for the same product says to the company proactively, you should think about setting up a cohort expanded access program it's inefficient to have these one that's not something that's required by regulation that's the FDA taking initiative I think you could use that same sort of logic of FDA taking initiative to do things that just makes sense to say if we ever start having an expanded access program that looks like it's running out of control and and cutting off the lifeblood of trials that FDA should say to the EA sponsor, you know we're going to start tapering you down. We, we got to do something, and you know, we're going to give you warning this isn't going to be immediate switch off, but somehow we got to start raining this in because we have to prioritize the trials now how exactly you formalize that I don't know but I think that's a learning that I'm taking away from this. Now the current state of affairs with the COVID vaccine in the US there may be some confusion around what's happening so was it approved what is this like emergency exemption mean. What's what's the status right now. So I'll go and Aaron can correct me so. So yesterday was an advisory committee the advisory committee recommended for emergency use authorization for the Pfizer vaccine. That's not an actual emergency use authorization that the FDA still has to make a decision and it probably will in the next couple of days. And did I get that right. Yes, that is right. And as far as I know there has been no use of the of any of the vaccines through expanded access that any of the experience with the vaccine thus far has been through the clinical trials that the various programs have been with the funding with government funding and organized. That's my understanding is that there's been no expanded access of any of these vaccines use now some of us have argued that rather than doing an emergency use authorization you should open these cohort expanded access programs and take care of your high risk populations that way in order to not absolutely destroy your trials but I mean obviously the political world has moved beyond that as a viable idea at this point so. Another question is important to just point out that emergency use authorization is distinct from a formal approval of a drug. And that would only occur after a, you know, a formal licensing application and a much more extensive review of data. And that's really important on that and this goes back to your medical professionalism question and education and whatnot. One of my colleagues, Holly Fernandez Lynch at UPenn and I have been deeply concerned about the fact that people are going to think that this physicians are going to think that this is an approved vaccine, which it's not. This is eligible for off label use. So if the emergency use authorization says 16 and up a physician normally with an approved drug could say you know well in my judgment this 15 year old needs it and I'm going to give it to them. You know just because I think the risk benefit ratio bears me out you cannot do that for an emergency use authorization that is illegal use of a product so I think that's something that we really need to make sure people understand. We had a question that came in I think it's a question for clarification, are manufacturers allowed to charge patients for drugs and minister via expanded access or both expanded access and right to try allow you to charge direct cost so that is basically the cost to create you know that allotment of drug you don't get to say well it cost me $5 million to create the drug through R&D, you know you just have to say that the purchase price for me to make this, you know, vial is $15 you can pass that on to the patient. We also pass on a tiny little bit for like shipping and handling and stuff like that. But that's, that's one of the reasons that led us to the crowdfunding website because if you have something that you know has to be overnighted it has to be below 80, you know 80 negative it has to have an actual nurse or clinician accompany it you know all of those things start adding up cost. So whereas there's a limit, you can't profit off the patients it still can be fairly expensive. Okay. So this question must have come in during the discussion of the US situation with the vaccine. What do you think about the UK that's already sort of vaccinating people. Does that mean that they're so so much further ahead in the regulatory sense than we are. Well you heard Dr Fauci comment on that in a uncharacteristically undiplomatic or in politic set of criticisms that the premature EU equivalent in the UK was in some sense meant to one up us here in the United States. Dr Fauci then backed, you know backed off that a bit. You know, the, the, the UK presumably had access to lots of the same information they, you know, exercise their own judgment. I think there's a certain PR advantage to being first, and that may have played into it. But then of course, what we also learned was that in the first day of their vaccination campaign. There were two episodes of severe allergic reactions in two individuals who happened to have a history of severe anaphylactic like reaction so much so that they carried epinephrine pens with them, and that sadly, however, has thrown an enormous amount of uncertainty into the mix. We're very worried about vaccine hesitancy here, which is part of the reason why the trust of the public in the regulatory process is so important, and that's another cost. And as Alison made the point, there are societal costs that have to be weighed against the individual rights. And I would argue that in the right to try legislation, the worry is that the societal costs are significant and they are subjugated to individual rights. Okay, so we have, let's see, a few more questions coming in. So, Dr, they've been how somebody asked that will pay, you mentioned that report the annual report for the RTT. Will patients get access to that and who was supposed to get that report anyway, what was the report aim to do. Well, the reason why no one's reporting to it yet and why I can't really answer that question that well is because the FDA is still making its rule. So it had a, you know, sort of a tentative rule put out for comments, there is a comment period and now we're waiting for the revised guidance so I think we're still waiting to to hear the answer to that I assume some aspect of it will be public facing. I'm not sure the actual like, you know, serious adverse events or, you know, they wanted things like, you know, the lot number of the drug, etc. I'm not sure any of that's going to be public facing but I think just the high level, you know, for uses in the last year will probably be public facing. I just don't have a date for when that's going to happen. Okay. I have a question for you so in the published piece that Allison just mentioned during our presentation. They did an analysis of crowdfunding, you know, sources to kind of see what where some of the activity was around people seeking these treatments and a lot of it had to do with core blood treatments for autism. And I know there are people in the audience who just might think well, I thought that core blood was safe. And I thought it was already being used medically. Can you explain to folks why that's why there's probably no evidence to show that core blood will work for autism or is there is there any way to tease out the possibility of that kind of intervention. There have been some clinical trials, especially conducted by Joanne Kurtzberg at Duke who has been quite rigorous in taking these interventions through a rigorous regulatory pathway that's this, you know, Duke is a frontline academic medical center they have good institutional review. And these trials have been conducted with with rigor. And that said, I think, many of us in the stem cell community scratch our heads at attempts to use cord blood for something as complex and developmental as autism. We are at a loss to even come up with a reasonable clinical hypothesis for how this intervention might work. And if it were to show some score in a clinical trial, how would we optimize it if we can't understand its mechanism and we can understand how then we can understand how to improve the treatment. So cord blood is one of those areas that has been subject to a very, very broad array of uses, almost none of which have anything to do with what we know cord blood stem cells or cord blood components actually can affect. One of those examples where, you know, ignorance seems to trump the rigor. And I think it's a it's a sorry, sorry statement about the nature of clinical clinical work in that area. Well thank you for that answer I think we have time for a couple more questions this questions for Dr Bateman house. The respondent says we see that you're currently working with at least one pharmaceutical company to help address some of the issues around compassionate use requests that they receive. Is it common for large pharma companies to establish such relationships with outside biotics experts. Do you see a future where each pharma company establishes some kind of robust biotics division or department internally. Wouldn't that drastically actually do you think that could be done considering the potential bias etc. Most large pharmaceutical companies have bioethics boards their academics or other people that they, you know, hire as consultants and convene, you know, once or a few times a year to ask them sort of broad policy questions. What I do with Jansen and what I think the question is probably leading towards is, you know, a closer, you know, specific guidance of, you know, we have these requests, we have more requests than we can fulfill. I think we should give access to if we can't give access to anyone. And I would say yes there's a growing reliance on outside bioethics people for that so I can tell you when we published our pilot study with Jansen. We had numerous companies call and say would you do it with us. And you know we had to say we're not consultants we're academic researchers and, you know, sorry, we've done the study we came up with our conclusions we're not going to be able to do this for you. If there is a void, it will be filled and I do know that there are other bioethics groups out there that have taken on that role for other companies. Excellent. So one last question for the TV and I'll post this first to Dean daily. It looks like extended access is the way to go. Do you think there's anything that needs to be approved upon in that process, would you recommend any tweaks to the process or do you think it's the gold standard and and really it stands on its own. Well, I think the expanded access, especially as delineated by by Allison has been put forth with a tremendous amount of or a tremendous balance of compassion and rigor. But I, I want to say that, you know, there really is no substitute for our ongoing efforts to improve the rapidity of innovation and clinical trials to base our clinical trials on stronger and deeper mechanistic understanding of these interventions so that we can be comfortable that we can predict efficacy and that we can really understand better the various safety challenges. I just think I'm a huge advocate for ongoing dependence on randomized clinical data done as quickly and efficiently as possible. And I'll say I'm a huge proponent of expanded access but only for people who don't fit into the trials so you cannot, you know, as George was just saying the trials are really what's going to give us the most societal benefits so you can't cannibalize the trials for expanded access but I do think that there's a role for people who cannot get into the trials for whatever reason and who are not going to be able to wait and have no other valid option I do think it could be better though I think. You know, so I do interviews with physicians and frequently they're misperceptions or misunderstandings about what it is so I think there's a massive educational need out there. And then I mentioned earlier that there's frequently a lot of paperwork involved and it's not necessarily FDA paperwork so when you talk with a company who says, Sure, we do expanded access and you say okay what paperwork doesn't involve and they say oh well we have to have a trial site agreement, you know, a trial site agreement is a massive you know, chief of papers that has, you know, involved lawyers etc etc and when you have someone who has 24 hours in which they have a window to get infused with something. It's just not fit for purpose so I think we need to do some work on streamlining the process. Not on the FDA side I think the FDA side has done all that it can do and more I think we need to talk about the wraparound of the institution and the sponsor. Thank you. It puts a heavy onus also on reducing bureaucracy. I mean I think that's really what Allison is getting at. I mean when we think back on the history of antiretrovirals when first introduced for HIV patients. You know, physicians and scientists understood the mechanisms they knew that these would be impactful medications and it was incredibly frustrating to have the kind of regulatory burdens that kept treatments from patients we saw it with. I think we always have that frustration we have to keep working to streamline the regulatory process but we can never undermine the importance of evidence that that has got to be critical. Well those are wise words to end with thank you so much for out of time I'd like to thank our two speakers and on behalf of Aaron Kesselheim and myself I'd like to thank our audience for joining us and for your questions. We look forward to seeing you next semester in both our consortia. Have a great weekend.