 as you're of introducing our next fireside chat, which is between Doctors Bill Chin and Rob Califf. And I'll introduce Bill in a second and I know Bill you'll have some words to introduce Rob, but I have a chance also to perhaps say a few things about Rob. We're just so privileged to have Rob stepping in in a second tenure as FDA commissioner, first under Obama and now under the Biden administration. Rob has been a leader across academics, across industry, and of course within government. And he's been an advocate for science and for high quality clinical trials and for patients. He's a clinical trialist by nature and has been an outspoken advocate for the use of real world evidence using the same disciplined approach that he and others and many of us have used in the clinical trial landscape. And as a human being and ultimately a patient we're all patients, we all should be comforted by the fact that Rob is in the most senior position of policy and regulation of drugs because he really has all the right mindset and he holds all of us accountable in industry, but also in academia. We all have to step up to ensure that medicines that there's innovation and that medicines are delivered to patients, whoever you are, whatever you look like, wherever you live, whatever your socioeconomic means are. So Rob, it's just such a privilege to have you as our commissioner. And it's of course a privilege to have you joining us. You're so engaged and you're outspoken in so many different forums. So the USAIC is thankful. And then I get to introduce again, my friend Bill Chin who's been a stalwart on USAIC part of the board. And since the inception of this group has been involved and prior to me was the emcee of this forum. Bill is also versed across industry, academics and government. Bill was a professor at Harvard Medical School. He's an endocrinologist, a translational expert. He spent time at Lilly and spent time as the medical director at Pharma. But what people don't know is Bill was also on the scientific advisory board of my company, Takeda, when I first joined. And for the first few years of my tenure there was a great mentor and supporter of much of what I started with in Takeda. So Bill, I will hand it over to you. Thank you very much, Andy. Good morning, Rob. Thanks for joining us today. You know, you don't need any more introduction for sure. I must say that you look good. So that's that. The format today will be what I call a moderated fireside at Rob. I have colleagues who will help me with some of the questions and I'll call on them when appropriate. So may I dare say, Rob, you are the Grover Cleveland of FDA commissioners. I think some will get that. But Rob, this is a good thing. And you've been through and I will paraphrase again the best of times and the most challenging times. The good, there are great new medicines for patients in cancer, autoimmune and rare diseases. The bad, the pandemic, which you live partly through, high profile AD medicines and most recently, methicrystone. You lead an agency that has oversight responsibly for over $2.5 trillion in US consumption or 20 cents for every dollar spent. And you might sort of say that's actually underestimating it. So Rob, with this responsibility, are you having a good time? Well, Bill, first of all, it's good to be with you all. And I'm looking here, seeing my good friend, Noresh, who I haven't seen in a while. And I will note, we're planning a trip to India in the fall. So I'm looking forward to that. Having said that, I don't describe it as having a good time, but I would say it's a fulfilling time. At age 71, I was having a good life living under the Golden Gate Bridge and working at Alphabet and the call came to serve again. And it's very hard to say no when it's so important. So it's not exactly the same as playing golf every day, Bill, but it's very fulfilling and the work is rewarding and challenging. And as I'm preparing for the pandemic prepared and as hearing tomorrow, you know, it's a good test of whether I have my mental facilities with me to deal with the challenges that we're currently facing. Very good, Rob. We agreed, actually, before this, not to talk about Method Pristone, because it's very name-like statements about, so I would like to ask at this point, what else keeps you awake at night? Well, Bill, I was an intensivist cardiologist for 30 years, and one thing you learn doing that is you can go to sleep at the drop of a hat. So nothing keeps me awake at night. If you ask me what I'm most concerned about, I think it's a division in our country which plays out in so many different ways in which I'll be facing tomorrow and another. Hearing, which is fundamentally threatening the basis on which the authorities on which an agency like the FDA depends to be able to do its job. And well, I can't talk about Method Pristone. I think everyone knows, because it is in a court case, everyone knows I think the circumstances there. And I am authorized to say we're concerned about the undermining of our basic authorities with some of the things that are going on now. Yeah, I appreciate that. Well, let's get on with some of these questions. I will start off asking about accelerated approval pathways. So these pathways for new drugs obviously have both advantages and disadvantages. And obviously this is very important to try to get medicines more quickly to our patients. So how do you strike the balance between providing prompt access to these treatments and ensuring there's enough evidence to prove safety and efficacy and very importantly to enhance public trust in the process? Well, you just said a mouthful. So let me try to dissect that. First of all, I feel like I always need to clarify that as FDA commissioner, I'm a political appointee and I think one of the most important things about FDA process is that decisions about individual products are made by full-time civil servants who are not political appointees and who are prohibited from having financial conflicts of interest of any kind. And part of my job is to shield them from the political interference, which can come into play. Having said that, I think everyone knows that my public record is to continue to believe that accelerated approval is alive and well. The American public spoken through its elected officials to create a set of rules that say when there's a serious disease, it doesn't have an effective treatment. There's a willingness to trade off some uncertainty for earlier access to a potentially beneficial drug. And the standard for most of the accelerated pathways is that it's reasonably likely that the benefits outweigh the risks, which is very different than a standard of the benefits are proven to outweigh the risks. And I think I was very pleased that Congress and the omnibus bill just passed recently gave us what I think we needed to tune up accelerated approval, which is to really give us direct authority to say you've got to enroll in your follow-up trial. And depending on the situation, it could be different. But we have the authority, for example, to say you have to start your follow-up trial before we make a decision to ensure that trial will enroll. There are certain times when that's not the right thing to do. We have discretion there by the law. And also sort of enhanced assurance that if a follow-up trial doesn't show that the benefit outweighs the risk or the company's not doing its job, we have authority to pull the drug from the market more efficiently. So those things are important, but I think the general idea that in America we're willing to take a bit more risk in order to get potential benefit in circumstances where there's not a proven therapy. And again, just last thing to say about it, I'm a cardiologist, so for diseases like coronary disease where there are a bunch of effective treatments, you don't want to take that risk and substitute something that you think might be better when you have something that already works. You need to prove that what you're offering actually is, meets that more general standard. Rob, we'll come back to that point just a second, but I just want to add on to this issue of the omnibus bill. There is in that mandate the provision that payers such as CMS may have more influence on the speed in which you do these confirmatory studies. Is that true and will it impact on your approach? So the first comment is that our authorities under the law are clearly distinct between FDA and CMS. We, our standard is safe and effective with benefits outweighing risk for the intended use. CMS's standard is reasonable and necessary for the population that's covering with it. It's basically its insurance product, Medicare or Medicaid. But I, you know my history, I'm an outcomes researcher, a clinical trialist, and there has been a gap in the American system where the evidence has not been filled in that I think people need. It's not our job at FDA to require that evidence before making a decision about safe and effective, but I completely understand that CMS could make much better decisions if it had better evidence. And so the part where we can contribute is really on two fronts. One is now that we're moving into the world of real world evidence and the use of electronic health records and we can do much more efficient larger trials that get the answers that we need. The baton handoff as I've called it between FD and CMS can be better if we sort of tailor our trials to begin to generate the evidence they need. And also we're talking with CMS more frequently so they understand the evidentiary basis for the decisions that we've made. So they're not going in blind. The analogy I've used is it's like a relay race. We don't want to run the first lap and then drop the baton in the dark and have CMS try to figure out where it is and pick it up and start running. We want to hand it off smoothly so they run the second lap. And they don't influence our decision and we don't influence their decision. But in my view, the continuum of evidence ought to be a real continuum, not something where everything stops with drug approval and then people don't get the evidence they need to make good decisions. Rob, I have Daphne Zohar, who's the founder and CEO of PureTech who has a question that follows on your comment about chronic diseases. Daphne? Thank you. So my question for you is regarding chronic diseases such as heart and lung diseases, diabetes, and also chronic conditions like depression that are serious, life-threatening and impact overall public health. Do you believe that the accelerated approval pathways could potentially be used for some of these chronic conditions assuming there are appropriate biomarkers? I believe that you used the words could potentially and how can I argue with that? They could potentially. With the caveats that I gave, let's take coronary disease where statins are highly effective and you have a new cholesterol drug. If there's a subpopulation where statins were ineffective and there are examples of this, that's a case where an accelerated pathway could be used for a subpopulation that was clearly identified. But you're really broaching what I think is a much larger issue where we all need to work together and think together about how to do this. For long-term chronic diseases, even where we have effective therapies, most of them are not curative. If you look at the residual burden of disease, for example, from coronary disease, and of course in this country we're seeing an uptick of stroke mortality and a total flattening of the coronary disease curve, we need new, more highly effective therapy, so we've got to work together on how to do it. But as I said before, up to this point we've done a really lousy job of taking advantage of the fact we've got 320 million people with electronic health records and more tactical capacity than any place on earth. And yet we're in the dark ages of clinical trials and outcomes research, particularly for long-term situations. And so I think this is fertile ground and we need to be discussing it. I'm very excited, at least in my colleagues in the federal government, there's a lot of interest. So we're going to be working on this, not just at FDA, but at NIH and CMS and DoD, the VA. There's a lot I think we can do to accelerate this field of endeavor so that we get more effective new therapies even when we have older ones that are partially affected. Thank you. Let me go on to the next issue. This deals with new therapeutic and analytical modes in drug development and we know them well. Cell and gene therapies, supportive AI, machine learning, model-informed drug discovery, and including also advanced statistical Bayesian-type models. So considering these advances, what steps has the agency taken to address them specifically regarding in two areas, expertise and then powerful? Well, okay. So you're asking more about what we're doing internally to be prepared for what's happening. Yeah, I mean, there's so much out here. So it's going to take an army and you have an army, but you know, you have a lot of people. Yeah, we're up to 19,000 people now, but in these fast-moving fields of computer science and tech, so to speak. I feel somewhat qualified, having spent five years at Alphabet about where the field is going and what's involved. People that are good in this field command high prices. I'll just put it that way and are quite mobile in the job market. So we are working on this. I will say I think the work that was done in CDRH on the issue of algorithms and digital product development I think really hit the mark for a lot of what needs to happen. So I think we're off to a good start, but we've got a challenge recruiting and retaining people with talent in this area. I'm thankful that the industry and Congress through the user fees and 21st century cures, which I had the privilege of working on and giving us special hiring and pay authority that doesn't exist in the rest of the federal government and that will help, but you know that that's nowhere near what a talented computer scientist can get working in the industry or even these days at universities with the options for startups and all that. So we're focused on it. Yeah, go ahead. I'm sorry. And we have a senator of excellence in CDRH focused on the digital world and I think we got some really good plans. If you know what's going to happen with generative large language models, please let me know. I would argue none of us know and the acceleration, the exponential growth of the generative component of that really offers an amazing opportunity, but also a real risk that things could go by in ways that would be hard to detect. Thanks, Rob. Since this summit has a focus on India, we have a couple of questions related to FDA and India and so I'm going to ask Dr. Nuresh Trihanda you know well, Medanta Hospital to ask a question. Nuresh, you're muted. Yeah, thanks Bill for the opportunity and I put me together with my good friend, Rob. Rob, you're very familiar with the yesteryear regulations of research in India and you know also that we disrupted in 2013 and then time to reframe everything and by 2019 we had a decent regulatory system which has been quite stable since then. So there are two things that keep coming up. One is the stability of the regime that has been established and being tweaked in advantage in favor of what has been represented as maybe pinch points for international trials and also for innovation to come to India and actually exploit the potential that exists in India. So given that the regulatory is now stable and then there are some concerns about the IBR and all that but we always had the impression that that has also been taken care of but if there is any tweaking to be done of course it can be done. But what I want to discuss with you is the prospect of conducting clinical trials in India and looking promising of course in this slide what is the agency's perspective on the importance of international regulatory cooperation and collaboration particularly involving clinical trial execution in India under international counsel for harmonization. So these guidelines are already established what can India do to be able to participate more as a deserving stable and integrity of the data that comes out of India. You are actually good to see how come you are not getting older that is what I want to know. We look good to each other you ask an 18 year old how would we look as an ancient. Those of you who wouldn't know this I was sitting in my office one fine day in Durham, North Carolina and my assistant knocked on the door and said there is a gentleman out here named Dr. Trayhan who flew from India to talk with you he didn't call me and tell me he was coming he showed up in person and our relationship went on from there and I did learn a lot from my time in India. I'll just say a couple of things Nourash number one you know that my history is I believe that clinical trial should be done everywhere because we all need representative samples in our clinical trials that includes the United States so I have a written record of saying I'm not in favor of offshoring that is using financial arbitrage to do experiments in other populations because the wealthy countries don't want to do the experiments in their own countries but if I lived in India I would want clinical trials done in my population just like if I lived in the US I would want clinical trials done in the US population and so the way to do that is to work together and in some cases do single global clinical trials like I used to do for a living that was my main academic pursuit but in many cases I think federated data is going to be the way to go because there are reasons you want to do sizable trials in your own you got 1.6 billion people now almost and there's a real need so the way to make federation work is to have an agreement on what the standards should be and while ICH is a great way to do the standards we are going to need to evolve to this more use of electronic records and more facile less expensive ways of doing research so that we can do trials that are adequate size not just to prove the principle that the drug might work in a certain population but to give the information that we talked about before what's the actual benefit across the population of eligible patients what are the risks across that population and increasingly I think the comparative effectiveness which again is not the primary FDA issue but as we work together federating this knowledge is going to be really important so I look forward to working with you all and like I say I hope to be there in the fall to nail some of our relationship the India relationship is critical to us and I can't mention that without mentioning generic drugs too there might be a question later about generic so I'll stop there but it's important for us to talk about that you know in this regard India is an ICH observer and not an active participant and so you know I guess the question would be how does the FDA work with India to try to encourage more participation so that these ICN standards could be more international so well we'll just need to spend time talking and figuring out the best avenue to make that happen and I plan to do that as I say with personal visits but also an emphasis I think it's obvious to everyone that the US India relationship is particularly critical right now to us for a whole variety of reasons one last question to India is the idea that there's been increased use of remote on-site inspections I guess part of that was pandemic related but this has led to more withheld applications and import alerts so how can the industry actually be better prepared for these remote inspections and the FDA empower the site for instance to actively identify and deal with these and solve these compliance issues and that is a that's a long you're asking a bunch of questions that we could talk for two hours about each question I'm spending a lot of time on this right now first of all I'd say the industry needs to support us as we go to congress and try to get the authority to ask for example for remote records across the board if you're running a quality shop in manufacturing a drug your record should be up to date all the time so there shouldn't be a problem with making those available that could enable the use methods including AI to target our human investigations where they're going to be most productive useful so I you know we're very much focused on systems quality as if you're running a manufacturing plant or you're doing clinical trials a question you know a spot inspection is just a spot inspection but we should be able to use surveillance across the board target the human inspections and keep the system at a high level of quality so let's come to the table and keep working on that part and parcel of that of course is we got to get over the idea that a spot inspection is also a punitive primary action sometimes when bad things are going on you do have to be punitive but the main purpose is to produce a quality product with accurate information and so just like companies should have internal auditing to make that happen corrective action should be something that we don't have to wait a year to come back physically we should be able to follow it virtually the way we're doing right now on this call yeah thanks Rob let's go on Susan Hochfeld has the president emerita of MIT I have a question about public bad and misinformation about medicines Susan thanks very much and Rob thank you for protecting our lives and keeping us all healthy listen you touched on this in your introductory comments but I really appreciate hearing more of your thinking because it's you know I'm quite confused about myself so the industry is mandated to provide truthful and non-misleading information about its medications and we want to trust the integrity of our governmental agencies but there is a very disturbing rise in the dissemination of inaccurate misleading information in all domains but certainly regarding FDA approved drug and I have to take this trend really complicates the sponsors responsibility to combat this kind of activity and even more importantly it undermines public confidence in biomedicine and therapeutics and I wonder if you have thoughts about how the FDA can help address this really quite harmful and corrosive phenomenon well I've been quite outspoken about this as you probably know and across the board I think you know I've said misinformation is leading cause of premature death in the US I actually believe that's true there's no way to prove it and so people have taken me to task like how can you prove that well I can't prove it but I think if you look at COVID deaths you know almost all COVID deaths now are occurring people are not up to date on their vaccination and have not gotten antiviral we look at heart disease opioids tobacco the leading causes of death they're heavily influenced by people not getting the treatments they need often being misled by people giving counter narratives we do have a draft guidance from 2014 that basically says if you're a company and you're being directly attacked with misinformation you have the ability to respond within the boundaries that we all know are the limits of the kind of statements that companies can make we're going to have to figure out with in a country where the first amendment is a first amendment for a good reason how to deal with I'm very taken with some things that have recently been written that our founders actually to go back historically apparently regarded the vast geography of the U.S. as an actual positive impediment to bad information spreading and taking over the country because it was hard to collude with bad information but now there can be collusion immediately over the internet that's before Twitter right and so the courts have their own views of this and federal agencies have limits but we can't let misinformation go and it includes pre-bottle that is dealing with it prospectively and also dealing with it as it happens so stay tuned we need to talk about this more thanks very much let's go on to a question that Chris Vebacher has regarding rare and ultra rare diseases Chris unmute yourself and thank you Bill Commissioner, thanks weekly I recently received approval for a product called Tefersen which will hopefully help ALS patients with the thought on mutation there are fewer than 500 patients probably in the U.S. and I really just discovered this coming into Biogen but it's been really moved by the plight of people with ultra rare diseases and I look at the resources that Biogen was able to put against that and develop this medicine but it's a pretty disvasive economic argument for pretty much everybody else and I was wondering when we have a population where it's hard to get a lot of data and hard to get a lot of statistical significance, any thoughts on how we can facilitate clinical research and I'm asking not only as commissioner of the FDA but as a clinical trialist yourself how do we actually find a more cost effective way to help these folks and get more medicines to them sure thanks Chris I you know like I said nothing keeps me awake at night but if I was going to stay awake at night of these people where now we all have good reason to think that science can provide if not cures palliative treatments that allow people to live longer with a chronic disease as opposed to dying in childhood for example so we don't want to hold that up and I think we firmly believe that at the FDA and I speak for the center directors here because we talk about a lot I'd say a couple of things first we're going to have to come up with new methods both for analysis and trial conduct for these ultra rare diseases and even for rare diseases because the way we do it now is too expensive and it's going to limit the number of cures but on the other hand I don't know if it's it's hard to put these things on a scale but telling someone you have an effective treatment when it's really not effective or the risks outweigh the benefits is heavily on our conscience at the same time so we all need to work together on the methods it sort of get and I'll say again it is time for clinical research to change to take advantage of technology the way other areas of society have done it and it's going to take a concerted effort but I'm highly excited about the potential for the changes at NIH for example that could help make this happen because for a lot of what you're talking about there's specialty centers and university academic medical centers where patients get referred and if we get them going with methods to take advantage of the electronic data they're already taking the amount of money you got to spend to verify the data and independently collect it and all I think could be dramatically reduced and then we've got to keep in mind that when we do things like gene editing we need decades of follow-up and if we tell you to do the follow-up the way it's currently being done one patient at the time with all the checks and balances it just puts it out of the realm of possibility because we don't know what the long-term effects of gene editing are going to be because of complex combinations of off-target genes that when you change one you don't know what's going to happen to the summative effects of the others that shouldn't hold us back we just need a measurement system that doesn't and it sort of gets at you know what I think the way people should think about the FDA in general we're like referees the rules are set by Congress in the United States we have input into the rule book which interprets the rules basically we're chairing on when someone does a good job and there's an effective treatment you see a celebration at the FDA just like occurs on the outside world when someone tries to cheat or not play by the rules or take shortcuts that could endanger people that's where you know as good referees we need to be vigilant so we need new methods thanks to the user fees we're hiring I think 150 new people in the Center for Biologics to work on this we're ready for public service send them our way we're hiring right now and we really welcome smart people coming in and helping us figure this out I think it's a really exciting time I mean things that we thought were impossible a few years ago now it can be done hey Rob we're just about out of time but I just have a quickie question okay you're coach K or coach S and you know what I'm talking about what would your top priority be in order to make sure that FDA is the winning team just off the top of your head what is the first priority that you would have I think the number one thing for me right now so let me just say two things one is we gotta get it right about what our authorities are to function the very basic authorities we have are under question right now we were heartened by the letter from industry about the court case with Miffy and you know I can't go into detail about that as we said but given that the number one thing is communication we got 19,000 people we got all sorts of people taking shots at us every day people have a right in the United States to criticize federal agencies they should in order for us to do well we gotta have our internal story straight communicating well internally and also communicating with the outside world which is hard to do because we have limits on what we can spend on people to help us with our communications so translation of science into plain English and I'll add now Spanish which is really a requirement in the United States absolutely essential that we have to get better but it's just as important internally as it is externally well you mentioned Coach K I had a situation the other day inside the FDA where I said if this were Coach K he would say show up at my house at midnight tonight and you're not going home until we got this sorted out until we're all working together that's the way we're gonna say that's good news hey Rob on behalf of the summit we thank you we've already thank you and your efforts on behalf of all of our patients but we appreciate your time and comments and perhaps you'll come back and visit again with us sometime oh yeah so Bill thanks and I do want to mention in the vein of referees celebrating two Alzheimer's results released today this is just magnificent for a disease that's affected so many people and it's not just these results they're very consistent with the results that we had already seen so we are we are cheering on here at the FDA you know we'll have to see as you know we have to look at the data when it comes in before making a judgment but if the data look as good as the press release this is really really exciting thank you Rob take care thank you Rob just in time for us Rob this Alzheimer's is just in time for us well thank you very much Bill and thank you very much Rob and I love the idea of us having a chief referee in the government and actually if I use an umpire signal it's this that fireside chat as baseball umpires do that was a home run it was over the wall so thank you very much Bill and thank you very much Rob so let's move now before we move to our next panel let's move to our next polling question and if I could have our folks pull that up so really simple following that panel in the next year the number of accelerated approvals will A decrease B stay the same or C increase we'll look forward to hearing all of your thoughts so please please participate in the poll let's pull up the results of the polling question that we just had please alright great actually uh again optimism in our audience which is terrific to see so um 50% of those polls think that over the next year the number of accelerated approvals will increase so that's really terrific to see that optimism