 Hi everyone. I never really imagined that I would be on this stage. I've only been involved about four years in this whole area. Then it came about from a personal situation with a family member who had a profound adverse drug reaction to SSRIs. And I think that that really turned my attention away from working on many other aspects of accelerating patient access into this area and seeing the promising research that was being done. So we are going to talk about, if I can see how to do that, how about that? Yes. We're not going to talk about regulation to start because regulation is just a path to patience. So we really want to talk about patience and patient need. A friend of mine recently told me that what does the word patient mean? It means the one who suffers. And so if you can look at this slide and the various facts and figures, you see there's a lot of suffering. And I think that this is really important. So these are statistics. The number in 2005 at the bottom 260 billion has now been recent study. You're looking almost doubling that in a little bit over 10 years. So the suffering is increasing. And so as we talk about this, what is the path to relieve suffering in this area in mental health? It's regulatory access. That's the only path that's available to us, as Rick said. There aren't any other magic paths. If we want to serve patients, if we want to support, we have to do our homework and use this path. So I'm going to talk a little bit over the next 10, 15 minutes. We're going to cover 140 years. And so hang on. And we're going to talk about regulation and a bit of what it is. It's a capitalist dilemma. Regulation is really a rule sets a procedure to guarantee conduct and to deal with conduct. Because sometimes when we are creating new things and believe in them, we just get a bit over-enthusiastic. And over-enthusiasm sometimes leads to conduct issues and conduct errors. And so this is all about regulation as a really interesting topic for wonky people. And it is something that really focuses in on this question of how do you regulate a public sector benefit, health, wealth, so banking and pharmaceuticals when they're produced by private sector innovation? How do you do that? And so this is two things I want you to know. One is it's a requirement in capitalist societies to have regulation. And number two, it's responsive. Some people might say it's reactive. Rarely is it proactive. So I'm going to start our little history tour right now, but do it a different way. So there are four aspects that we have to pay attention to in contemporary world right now. One is the claim. So what are we saying? If you have no claim, if you have no sense of benefit, then you needn't go to regulation. It's not a requirement. It's only when you make a claim that's important. Here is one of the claims that led to regulation. It was snake oil in the United States. And this could do anything and it could relieve instantaneously. It almost sounds like psychedelics. Safety, efficacy and quality are the other three elements that are required. And I'm going to talk a little bit about the evolution and growth of this. But this really, the whole notion of regulation started in the 1800s. The major thing that really kind of galvanized this was in 1937 in the United States. And this really led, this was the first public health issue. And you know, people created this sulfanamide elixir. It was something that was actually used for infection, et cetera. And unfortunately, they just happened to use diethylene glycol, is part of the formulation, which is a poison. But they didn't do talk studies before, toxicology studies. So this is the first time where we have a regulatory system that's responding. It's actually, no, there was a poison used in this and we have to actually take a look at toxicology. It's not just something to say, whoops, and 100 people die, right? So these are the kinds of responsiveness that you start seeing. The next thing that Rick mentioned was, in late 50s, there was a sedative, a sleeping pill called phyllidomide that was marketed predominantly in Europe initially. It was a German company. And that was used at that time, fairly primitive clinical trials. And they just didn't happen to test phyllidomide on pregnant women systematically. And you'll see in kind of a testimony to the resilience of the human spirit, a bunch of children who were born because of that with birth defects. So this kind of brought about a huge, huge public response about, are we really doing the science that we need to? Meanwhile, same time period, psychedelic research was peaking, so to speak. And we had sandos at distributing LSD and psilocybin in an investigational format. So anyone who wanted psilocybin or LSD could write and get access to this, because this was being marketed, go try it out, see what it works. You know, if you're a physician, you can apply it. And so it's really important that two years before Timothy Leary ever stepped forth on the stage, sandos actually started to restrict the use of the delivery and distribution of these medicines. And then we had Timothy Leary. But there was a regulatory impact beforehand. And this really led to the confluence of phyllidomide and psychedelics led to a whole host of new regulations. And the new regulations are all about how do we think about this question of what's our public responsibility in terms of safety? And a new topic was added in 1961, very recent, in the scheme of things about efficacy. Does it work? Now, it's a fairly low bar in the United States. Does it work better than a sugar pill? Well, I guess, you know, that's still a bar, so useful to look at. But this was the birth of placebo-controlled trials. And for the next 30 years in regulation, so now we're going from the 1960s to the 1990s, things were really moving forward. And you had this, as Rick pointed out, this fundamental balance that regulators look at. Is there more risk or more benefit? And how do they relate? And if, in fact, you have more benefit than risk for a particular patient population, Bob's your uncle, you go out and you do it, right? You have access to that patient population. So that's kind of where regulation was. And it responded. There was another inflection point that's critically important for this audience and this topic, which is in 1991, kind of we had the AIDS crisis in the late 80s, there was an impact probably for the first time of people protesting about regulatory process. And this was the ACT UP group in the United States across Europe. And this led to a view that for critical conditions where there's a high unmet medical need, where people are suffering to go back to the beginning, we need to accelerate the review of drugs, in this case for life-threatening diseases and significant unmet needs. So this construct of acceleration didn't really take place until the 1990s. But it's a really important feature of today's regulatory environment, particularly when it comes to unmet needs. I want to also point out, as Rick said, that there is a learning system that goes on here and philitimide is in the market right now. It's not for use in pregnant women, obviously, we've learned that. But it is actually probably one of the most effective treatments for leprosy. By the way, how do you learn that a sleeping pill is useful in leprosy? Well, people who take it, who actually are looking to gain relief in sleeping and have leprosy, and you see that the leprosy goes away and there's an effect of the drug. So there is learning that takes place in the real world. And that's actually where real learning happens. And that's why there's this whole view to accelerate access. Okay? Now, another thing that happened, another element that really has shaped today's system, the system that we're about to lean into the visible future for us. This is really about the post-launch safety crisis in the 2000s. So I'm using one example. There are many examples, sadly. This one is on Prozac. It's the use of Prozac or SSRIs with people who are young and vulnerable to suicidality. And the fact that it can actually increase suicidality. Now, the problem is that the clinical trials were not done in a shady way. You know, they were just done. But there's a limitation in a clinical trial. The current compact, the current deal with pharmaceutical companies and society is really straightforward. It is, you develop a tremendous amount of research. You go through different stages, expand the research. You then are granted a ticket and that ticket gives you permission to sell the medicine. Now, that was a human decision. What if we had a different decision? A decision that said, there's no way we can figure out all the uncertainty that's possible. It just isn't possible, right? So let's say we have a clinical trial of 5,000 people. But we have an adverse event like suicidality that shows up every 5,100 people. So what you end up having in this situation is a medicine that goes to market. It goes from 5,000 to millions of people. And then you discover the uncertainty, the adverse event that you couldn't detect in your trial because the signal wasn't there, because it doesn't happen frequently. So this scale-up process is really important. And it's also where a lot of uncertainty happens. This was the birth of REMs. So what Rick talked about earlier around the risk management, this is when this really started to come into play is when uncertainty exists and we can't get it all out of the system. Now, we could have two different options in this world. One option would be to say, well, what we need are bigger and bigger and bigger clinical trials, which means more and more expensive, more and more delays, and that fights against the fundamental prospect of if we have an innovation that's a technology that could be helpful to people, we want them to have it. We want them to have access. So what if we change the deal? It's just an agreement. What if we had a different model that could start emerging, which says, actually, the deal is you have to demonstrate early signals of safety, early signals of efficacy, and then very progressively, very systematically, for the remainder of the life of the medicine, the patent that you have, you have to step carefully and you have to collect data. And instead of having this giant free-for-all after you've received information, what if you have a public responsibility to collect and improve public health by virtue of your medicine? So you can just make a different agreement. And I think that this is a future, it's a visible future. Now, the last element that goes into this particular world at which we're standing right now is the financial crisis of the 2007-2008. This made it very clear that there were some times that health systems simply could not afford their innovations. You know, cancer medications, governments here in Europe, very, very focused on this question of how the heck do we provide access to medicines that are so expensive that I can make a decision of an expensive cancer patient for one patient, a medicine for one patient, or insulin for 5,000? How do I make that decision, right? That's a very fundamental decision a government has to make. And you'll see that regulators in Europe are really thinking deeply about this. And I think that's a really important issue. So to summarize other things that are happening, I never knew it until probably six or seven years ago, but there's something called regulatory innovation and regulatory science. We think of this, the pharmaceutical industry always talks about regulatory hurdles as if it's something to get over. Well, actually, this is an evolution of how do we deal with a compact, the social compact between developers of products and the public. And so in this case, what we're seeing is that there's some, the first two articles are written by the leadership of the European Medicines Agency. And those are really focused on the risks of risk aversion. Who would imagine that a regulator would be writing articles about the risk of risk aversion. But that's precisely about not having patients receive the benefit of technologies. Another one is this notion of adaptive licensing and adaptive pathways that I talked about a moment ago. What if we could adapt and go into the market with the responsibility to collect data and be in the real world faster? Really important. And then the last trend that I think is very critical is this notion of, I think governments are very tired after all of the payment, all of the financial crisis. Do we pay for outcomes or do we pay for inputs? Do we pay for pills? Or do we pay for better people, healthier people? And increasingly, the new business models that we can leverage are around outcomes, not about inputs. So with that, we also are coupling into psychedelic assisted therapy. So that takes us to today. Where are we going? Well, these are the quality, the aspects in 2016 that are required to have an unmet need in a well-defined patient population to have safety, efficacy, quality production, comparative effectiveness. These themes went through Rick's presentation. These things, the last one are particularly important here in Europe. And I will say that despite my accent, we believe that Europe will be the leader in this type of process. Now, there is a need still just to kind of bring us back to where we stand today. You had a huge increase in psychopharmaceutical spending from 1988 to 2008 in the National Institute of Mental Health. These are US figures. But the problem has become worse. I'm not going to get into, you know, getting into attribution errors of why that's the case. It's multifactorial like so much in life. But it's getting worse. There still is a need. So that's tick that box. These medicines when used in clinical research, whether you see the wonderful data, we stand on top of all of this work that has happened in the past years. So, you know, it's just tremendous work that helps us all is these medicines are among the lowest in harm potential. And you'll see that adverse events are serious adverse events are largely missing from the entire field of research thus far. When you talk to regulators and so forth about adverse of serious adverse events, they talk about death. So I think it's really very important that we put this into context in terms of that safety issue. Efficacy, what really is attractive to regulators and interesting to regulators is this pattern I've just picked too randomly, but you've seen more and more of these charts today. What happens? What is the mechanism? Why are we taking this medicine at a point where in fact, a medicine assisted therapy, and then a downtick in whatever symptom, and it goes out for a while. That's really interesting and distinctive and promising early signals, pharmaceutical companies, everyone looks to this early signals. So again, we have safety, efficacy, these are the critical things, quality production, Rick's doing this, others are doing this where there will be GMP meeting EU standards so that we actually have medicine that we can use, that we can use reliably in trials that have appropriate standards, they meet good manufacturing practices. And we need to start doing studies that actually look at comparative effectiveness relative to usual care. So that's really looking out toward the future. Now, strategy, how do we move forward? I'll do speak quickly on this. It's the art and science of planning and marshaling resources. Well, as you know, this area has had scant resources. We need to look at that deeply. Because the numbers here are really small, the need is huge. Just think about any of the numbers you've seen on any of these slides today in terms of the unmet need. So that means that we need a strategy. What might that look like? Well, it could be to identify a patient population with a benefit risk profile, one where there's more benefit than risk. People often look toward people toward the end of life or in a life threatening situation. Okay, we have that precedent. But also in this new model of adaptive pathways, one requirement is that you actually can adapt and grow into other populations. So new data, grow, move in more, more patient so that we have a kind of natural expansion of access to patients. Manufacturer, we just need to do that. Work with regulators and HTAs. What's happened? Well, I've been involved in these new collaborative processes between regulators and pharmaceutical companies and other stakeholders, health systems and so forth. There's a real hunger to provide not only access to medicines more rapidly, but to look at new models of doing that and collaborating between regulators and health technology agencies. So we have to start using those processes collectively in this room if we're interested in patients. Papers are terrific. They're really critical. But if we're interested in reducing suffering with patients, this is where we have to go. And then of course, we have to start doing multi-country multi-site clinical trials for authorization. And that has to be done at scale. It has to be done with the leading edge methodology and remembering that everything is innovating simultaneously. We have regulatory science innovating and we have neuroscience innovating. So I think that where do we need to coordinate our action? I'll stop over the next two minutes. We really need to have much more systematic policy dialogues across a whole host of stakeholders. It's the only way forward. We need to educate dispel rumors. We need to dispel misunderstanding. And we need to really look at how do we move forward together. Therapist training and support. It's critical. If we're going to scale, we need to understand just as Rick has pointed out, we need to develop a systematic way to meet the need that has to start now. Care pathway development. Well, this is a big mouthful of words, but what health systems are looking for is how do we take a patient who has a need and move them through a care pathway so that they actually benefit. So we need to develop these care pathways for this type of science and to look at how do we care for patients in the future. And lastly, translational research, translational research, translational research. We always have to be measuring, looking what is the impact, what's the benefit. So if we do all that, where do we get? Well, we have policies that can work. We have professional standards that like Rick talked about where people actually are in condition to deliver this safely, effectively. And we're looking at how do we get paid for outcomes in this new world where we're creating outcomes and hopefully a far more cost effective model than we have had with the traditional approaches with the pharmaceutical. Now, what do we need? Moving forward on this path, we need strategic financing. What I mean by that is there are new models for large scale financing and we need to look toward global health where we have HIV AIDS, we have maternal health, etc. There are many new financial vehicles who actually fund this and they're all funded based on the process that there will be a return. The return does not have to be usurious. It does not have to be high, but it has to be present. So this is where the outcome based models of reimbursement are important. We need open science. This is of value. I think it's important. The Dutch presidency last week advocated open science and that means that we really need to be sharing data so that the rising tide lifts all boats here. This is not something that I think we can withhold. And lastly to move forward, we need collaborative partnerships. Ones that really look at the breadth that you just opened up with today of all of the different partners, all of the different parts of society that need to come together and work together. So I think that is pretty much where we are. I think we need to, we owe this to patients and we owe this to each other to look at how do we do this. And we formed a not for profit medical research organization to help out with some of these items.